Added: Kellymarie Luellen - Date: 14.01.2022 23:14 - Views: 47616 - Clicks: 8277
Context Methadone hydrochloride treatment is the most common pharmacological intervention for opioid dependence, and recent interest has focused on expanding methadone treatment availability beyond traditional specially d clinics. However, despite recommendations regarding effective dosing of methadone, controlled clinical trials of higher-dose methadone have not been conducted.
Objective To compare the relative clinical efficacy of moderate- vs high-dose methadone in the treatment of opioid dependence. De A week randomized, double-blind clinical trial starting in June and ending in October Main Outcome Measures Opioid-positive urinalysis and retention in treatment. By intent-to-treat analysis, through week 30 patients in the high-dose group had ificantly lower rates of opioid-positive urine samples compared with patients in the moderate-dose group These differences persisted during withdrawal from methadone.
Through day no ificant difference was evident between dose groups in treatment retention high-dose group mean retention, days; moderate-dose group mean retention, days. Conclusions Both moderate- and high-dose methadone treatment resulted in decreased illicit opioid use during methadone maintenance and detoxification. The high-dose group had ificantly greater decreases in illicit opiod use. It has good oral bioavailability, can be dosed once per day, suppresses opioid withdrawal, and provides cross-tolerance to the effects of other opioids.
Outpatient treatment combining daily methadone plus counseling has been available for more than 30 years. Despite methadone treatment's extensive history, controversy regarding optimal dosing persists. Early clinical trials assessing the dose-related efficacy of methadone produced conflicting5 - 8 and by the late s surveys of dosing practices found some methadone clinics having average daily maintenance doses of less than 30 mg, and other clinics using average daily doses of greater than 60 mg.
The purpose of the present study was to compare moderate— with high—daily dose methadone in a contemporary population of opioid-dependent patients. In a clinical trial conducted at the same clinic, a comparison of low— to moderate—daily dose methadone showed dose-related differences in treatment retention and rates of illicit opioid use.
Patients seeking opioid dependence treatment were enrolled in the study. Eligibility criteria for participation were age 18 years or older, current intravenous opioid dependence including documentation of at least 2 methadone detoxification attempts or a prior episode of methadone maintenance treatment, a urine sample positive for opioids, and physical examination consistent with acute and chronic needle useno chronic medical illnesses, absence of major mental illness, negative pregnancy test result for women, and at least 1 month since the patient's last treatment at this clinic.
The study was approved by the institutional review board, and written informed consent was obtained. Eligible applicants were admitted to a week methadone treatment program and randomly ased to 1 of 2 methadone dose schedules. Group asment and methadone dosing were double-blind for patients and staff who had patient contact. During the first week of treatment all participants received 30 mg of methadone daily. Over the subsequent 5 weeks patients in the high-dose condition had dose increases of 10 mg each week, while patients in the moderate-dose condition had dose increases of 2 mg each week.
During weeks 8 to 30, participants were eligible to receive double-blind dose increases and decreases. Dose increases were made in increments of 10 mg and 5 mg for the high- and moderate-dose conditions, respectively. The maximum of dose increases was 2 ie, to maximums of mg and 50 mg of methadone for the high- and moderate-dose conditions, respectively. Increases were at least 3 weeks apart and were based on continued illicit opioid use as evidenced by at least 2 of the patient's last 4 urine samples testing opioid positive.
Dose decreases were ordered if the patient requested such, and appeared to be overmedicated or had 6 consecutive opioid-negative urine samples. Subjects and staff were not given details regarding the criteria for dose changes but were told dose changes were possible during the study. Participation at the treatment and research clinic was time-limited, and enrollees were informed of this and encouraged to engage in long-term, community-based treatment after study participation. Subjects and staff were unaware of the phases or details of the dosing schedule, and were simply instructed that all patients would be detoxified by the end of the 40 weeks.
Patients interested in applying to transfer to community-based methadone treatment were assisted by clinic staff. Patients who missed 3 consecutive days of medication were discharged from treatment. Patients were ased a counselor who set treatment goals and developed an individualized treatment plan, and received weekly individual and group therapy focusing on relapse prevention.
On-site medical services were provided by a full-time internist. Take-home medication was provided only on major holidays and for extenuating circumstances. Since the study sought to determine the relative efficacy of moderate- vs high-dose methadone, the primary period of study interest was the first 30 weeks.
Three primary outcome measures were reported: self-reported illicit opioid use, urinalysis toxicology, and treatment retention. Self-reported opioid use was assessed weekly for the first 12 weeks of the study, and then once every other week thereafter with the drug use questionnaire. The drug use questionnaire asked the of times drugs, such as illicit opioids, were used in the past week. for patients who remained in treatment to the end of the stable dosing phase the retained sample were used to examine possible time-course effects.
A total of subjects were included in this analysis; all in-treatment self-reported drug use data for 1 subject, who was ased to the high-dose condition and remained in treatment to the end of the stable dosing phase, were lost. Patients provided observed urine samples twice weekly Mondays and Thursdays. Two approaches were used to summarize urine.
First, the overall percentages of positive test for opioids, cocaine, and benzodiazepines were calculated for each patient through the end of the stable dosing period intent-to-treat analysis. Second, patients who remained in treatment to the end of the stable dosing phase the retained sample had their urine data summarized in 3-week blocks by calculating the percentage of urine samples positive for opioids in each block; these were used to examine possible time-course effects.
Finally, treatment retention was calculated as the total of days from admission to discharge, or to the last day of the stable dosing period day if the patient remained longer. An adverse effects checklist, as a secondary outcome measure, was reported based on data from the first 30 weeks. Patients rated symptoms for severity on a 5-point scale with a zero equaling not at all to a 4 equaling very severe. Forms were completed weekly for the first 12 weeks, then every other week for the remaining period. for constipation and sleepiness or grogginess are reported. Secondary outcomes for patients who entered the dose-tapering period weeks are presented here to characterize the relative efficacy of methadone detoxification.
The percentages of positive urine test for opioids, cocaine, and benzodiazepines were calculated for each patient during the detoxification period, and treatment retention during this phase was also determined. Power analyses based on effects detected in an earlier clinical trial of methadone treatment 13 indicated that 96 patients in each group would be needed to detect a medium effect size 0. The response of individual subjects was first modeled, and then the estimates for each individual were combined in a group analysis.
Treatment retention curves were compared using a Cox regression model. The percentages of positive urine samples for the intent-to-treat group during the maintenance phase, and for patients who entered the detoxification phase, were analyzed using analysis of covariance. Covariates used for multilevel analyses, analyses of covariance, and survival analyses are described below. The Tukey test was used for pairwise comparisons among means. The following descriptive statistics are reported for each group: the average dose of methadone from the beginning of week 8 when dose increases could occur to the end of the stable dosing period, the of patients receiving dose increases, and the of patients receiving dose decreases.
Patients' rates of in-treatment drug use may be related to rates of pretreatment drug use 24 - 26 ; therefore, these correlations were examined. Pretreatment opioid and cocaine use was assessed using the drug use questionnaire, and pretreatment benzodiazepine use was assessed using the past week drug use form, a questionnaire assessing the of days during the week that drugs such as benzodiazepines were used.
from these questionnaires represent rates of use in the week prior to admission.
In-treatment drug use was calculated as the overall percentage of positive urine samples for each drug category during maintenance treatment. Pretreatment rates of opioid, cocaine, and benzodiazepine use ificantly correlated with in-treatment drug use, so these measures of baseline drug use were included as covariates in all analyses.
Participants were randomized individually after being stratified on 2 baseline variables: presence vs absence of pretreatment cocaine use defined as either a cocaine-positive urine sample at the time of application or any self-reported cocaine use in the 30 days prior to admission ; and a low vs high level of pretreatment illicit opioid use defined as pretreatment self-reported illicit opioid use averaging no more than once per day vs more than once per day. The order of condition asments within each stratum was random, and asments were sealed in ed envelopes within larger envelopes corresponding to each stratum.
On the day of admission, a research assistant with no patient contact determined the patient's stratification, drew the next sequential envelope from that stratum, and ased the patient the dose condition contained in the envelope. Dose codes were entered into a database accessible only to pharmacy staff and selected research assistants with no patient contact. Sealed dose codes were maintained at the dispensary in case of emergency. No breaking of dose codes was required. All patients received identically appearing, individually prepared doses in a volume of 60 mL, labeled with the patient's name and date.
Doses were masked with cherry-flavored liquid concentrate Mallinckrodt. Patients ingested each dose under direct nursing observation and immediately rinsed their bottle with water that they then drank. Figure 1 shows stages of the trial. There were no ificant differences between the moderate- vs high-dose groups for variables listed in the Table 1and there were no ificant differences between the retained vs dropout groups for any of these variables. The retained group reported using opioids an average of 24 times in the week prior to admission Table 1.
During the latter half of the stabilization phase, the high-dose group reported using illicit opioids an average of 1 or fewer times per week, while the moderate-dose group was reporting use of illicit opioids an average of 2 to 3 times per week. All patients enrolled in the study the intent-to-treat population were included in these analyses, thus providing an overall measure of drug use through week 30 for each participant. High-dose condition patients also had lower but not ificant differences in rates of cocaine use Both the moderate- and high-dose groups showed a decline in opioid-positive urine from weeks 1 to 3 through weeks 4 to 6 of treatment.
However, the high-dose group continued to show a decline in the rate of opioid-positive test in weeks 7 to 9, while the moderate-dose group did not. Both groups had relatively stable rates of opioid-positive urine samples after weeks 7 to 9 of treatment. There was no ificant difference between dose groups for treatment retention. Through the end of the stable dosing phase daypatients ased to the high-dose condition remained an average of days, while patients ased to the moderate-dose condition remained an average of days.
There were no ificant differences between dose groups on self-reports of constipation or sleepiness or grogginess. For both measures, the most common rating was not at all. Ratings of sleepiness or grogginess as moderate, severe, or very severe were 3.
Patients in the high-dose group continued to have ificantly lower rates of opioid-positive urine samples There was no ificant difference between groups in rates of cocaine- or benzodiazepine-positive urine samples during this period. In addition, there were no ificant differences between dose conditions for treatment retention Figure 1. The average stable daily dose of methadone hydrochloride for patients who remained in treatment until at least week 8 was In the high-dose condition there were dose increases and 13 dose decreases. In the moderate-dose condition there were dose increases and 4 dose decreases.
This clinical trial examined moderate- vs high-dose methadone in the outpatient treatment of opioid dependence. show that both doses of methadone were effective in maintaining patients in treatment and substantially decreasing rates of illicit opioid use. The high-dose group had ificantly greater decreases in opioid use compared with the moderate-dose group.
When compared with the pretreatment period, both groups had substantial decreases in illicit opioid use that were clinically ificant. These self-report and urine sample are consistent with each other. Urinalysis testing has great sensitivity for detecting occurrence of any drug use, but little sensitivity for detecting declines in frequent drug use.
Single instances of drug use result in positive urinalysis for 2 to 4 days. Thus, 1 to 3 uses per week may correspond to this proportion of opioid-positive urinalysis test. An earlier clinical trial at this same site found clear and ificant dose-related differences between low— 20 mg and moderate—daily dose methadone hydrochloride 50 mg and found both to be superior to nonmaintenance detoxification treatment, as assessed by treatment retention, rates of illicit opioid use from self-reports and urine testing, and other measures related to drug abuse.
While dose-related differences were found for opioid use in the present study, unlike the earlier study there was no ificant difference between dose groups for treatment retention. from this study were analyzed to examine possible sex differences in dose response, and no ificant sex effects were found for any of the primary outcome measures reported here.
Similarly, were analyzed to determine if methadone dose influenced cocaine use, and no such effect was found. There were no ificant differences between the 2 dose groups in self-reported adverse effects. The frequency and severity of adverse effects were low for both groups. The relatively moderate differences between dose conditions in the present study are not inconsistent with earlier clinical trials with methadone hydrochloride that reported little difference in outcome at daily doses above 40 to 50 mg, 6 - 8 although more recent studies have generally found ificant differences between lower and higher methadone doses.
Because urine testing is a relatively insensitive means for detecting substantial changes in drug use, the differences between doses found for urine from this study can reflect substantial changes in drug use, especially when compared with pretreatment levels. Well-conducted clinical trials testing such high doses would likely be needed to support revision of those regulations. In the meantime, the from the current study provide evidence that ificantly improved outcomes can be achieved with daily methadone doses greater than 40 to 50 mg.
Figure 1. Randomization occurred on the day of admission to the study.Methadone 10mg high
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