Fourth, clinicians and the patient work together to find a stable dose. The patient and clinicians identify the dosage at which:. After the clinicians and patient find a dose that meets the criteria above, they move on to the Stabilization Phase. If the patient has not started to receive counseling, this is the phase in which they do. Federal regulations — and laws — require that anyone participating in a methadone program also receive counseling.
In some areas, participants are also required to attend support meetings such as Narcotics Anonymous NA or other state-approved substance use disorder treatment programs. Once the patient achieves a steady state of methadone in their system, meaning a consistent dosage that meets all treatment criteria, the clinician and the patient monitor the subjective experience of the patient to ensure the dosage is correct.
Some patients stay on the same dose for months or even years, but most dosages will require intermittent adjustment. This is also the period during which the patient focuses on addressing the root causes of their addiction, treating any co-occurring disorders that may be present, and making the lifestyle changes that accompany and support a sober lifestyle.
Concomitant use of benzodiazepines or alcohol see also Section 4. The risk of overdose increases most markedly when other central nervous system depressants are also used. If the patient shows signs of intoxication with benzodiazepines or alcohol, the dose should be withheld or reduced. Caution should be exercised for starting doses of 30mg or more. Exercise extreme caution if an initial dose of methadone exceeding 40mg is considered necessary. Specialist consultation may be advisable.
Top of page Stabilisation During the first two weeks of MMT the aim is to stabilise the patient so that they are not oscillating between intoxication and withdrawal. This does not necessarily mean that the patient will reach an optimum maintenance dose in that time and further dose adjustments may be required after the patient has been initially stabilised. Monitoring during the first two weeks Patients should be observed daily prior to dosing and an assessment made of intoxication.
If any concern they should be seen by a doctor before the dose is administered. Because of the pharmacology of methadone, to ensure safety, it is desirable that patients are reviewed at least once, and preferably twice by an experienced clinician doctor or nurse in the first week with a view to assessing intoxication from methadone. Dose increases should only be considered subject to assessment by the prescriber.
Assessment should include withdrawal severity see Appendix 3 , intoxication see Appendix 2 , other drug use see Section 4. Dose titration Stabilisation is about titrating the dose against needs of the individual patient. Results 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 assigned 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 results. First, the overall percentages of positive test results 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 results were used to examine possible time-course effects.
Finally, treatment retention was calculated as the total number 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. Results 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 results 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 number of patients receiving dose increases, and the number 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 number of days during the previous week that drugs such as benzodiazepines were used.
Results 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 significantly 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 assignments within each stratum was random, and assignments were sealed in numbered 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 assigned 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 significant differences between the moderate- vs high-dose groups for variables listed in the Table 1 , and there were no significant 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 significant differences in rates of cocaine use Both the moderate- and high-dose groups showed a decline in opioid-positive urine results 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 results 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 significant difference between dose groups for treatment retention. Through the end of the stable dosing phase day , patients assigned to the high-dose condition remained an average of days, while patients assigned to the moderate-dose condition remained an average of days. There were no significant 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 significantly lower rates of opioid-positive urine samples This may also explain the finding that low local heroin purity is associated with greater methadone needs.
Assuming those using less pure heroin achieve lower blood levels of opioid with each use, users in areas with low local heroin purity would experience withdrawal more quickly after each use and thus more frequently over time. Willenbring and colleagues [ 29 ] observed that methadone clinics with low patient turnover and a large number of patients who had been maintained stably in treatment for years had successful treatment outcomes on lower average methadone dosages.
Keeping patients on stable opioid dosages and limiting periods of withdrawal e. These results suggest that maintaining a patient on a dosage at which he or she experiences withdrawal symptomatology late in the dosage cycle, or repeatedly attempting to withdraw a patient from methadone, will not limit the need for methadone and may in fact increase the dosage of methadone needed to achieve abstinence over the long term.
Although it has been reported that some opioid substitution treatment clinics provide more methadone to their patients with chronic pain [ 30 ], this did not appear to be necessary to improve abstinence rates in our sample.
Even though chronic pain may be treated with opioid therapy, patients with higher pain levels did not require more methadone to abstain from heroin use. In contrast, having a diagnosis of depression or PTSD was a strong predictor of need for higher dosages of methadone. Our results suggest that patients with these conditions should be expected to require higher medication dosages, and thus, it may make sense to more aggressively titrate dosages early in treatment in these patients.
Although treatment factors are less likely to explain individual differences in methadone dosage needs, they likely influence who receives an adequate dosage to achieve abstinence. Treatment factors that result in reduced likelihood of receiving an adequate dosage will bias the population that achieved abstinence toward those who require lower methadone dosages.
Thus, dropping out of treatment at an earlier time and attending a clinic that encourages dosage reductions is associated with lower effective methadone doses. We believe that only those patients with low tolerance to methadone achieve abstinence early in treatment or when clinicians encourage reductions in dosages. Encouraging rapid dose titration early in treatment and discouraging attempts at dosage reduction or cessation should improve the percentage of patients who achieve abstinence.
The results reported in this study are predictive associations, but causation cannot be assumed. Also, the clinics participating in this study treated few women and younger patients. This may limit generalizability of the results. Although including patients who received LAAM during treatment did not change the study results, our analysis is not sufficient to conclude that the results of this study can be generalized to opioid medications other than methadone e.
Finally, because the study was observational, we cannot know that the dosage a patient received while abstinent was the minimal dosage required for abstinence. Some patients might have maintained abstinence on lower dosages.
We suggest that future treatment research investigate processes of dosage determination rather than specific drug dosages e. When there is large variation in individual dose-response relationships, overall dosage-level recommendations may not provide clinicians with sufficient information to guide treatment practice. We suggest that research that identifies the most effective process for determination of medication dosage may be more effectively translated into clinical practice.
The range of effective methadone doses for treatment of opioid dependence is broad, and treating clinicians should titrate doses to full effect in each individual patient. Dosing guidelines should include advice on appropriate processes of dosage determination. Patients with PTSD, depression, numerous prior opioid detoxification treatments or withdrawal episodes, and those who use low-purity heroin are likely to require higher dosages of methadone to achieve abstinence.
This is a sample of a consent form from one of our eight participating research sites. Consent forms from the other seven participating sites were similar, with minor modifications of formatting and language to comply with local IRB preferences.
The funding agency was involved in review of the MOST study funding proposal, but was not involved in other aspects of the study and manuscript preparation. We thank Catherine Hammons for her assistance with data analysis. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. JAT conceived and designed the analysis described, managed data acquisition, analysis, and interpretation, and drafted the manuscript.
JM conducted data acquisition and assisted with data analysis, presentation, and interpretation. JM and KH critically revised the manuscript for important intellectual content. Methadone is a legal and rigorously tested synthetic drug that acts on the same brain targets as heroin. Because methadone lasts a lot longer in the body than heroin, patients on methadone do not experience the extreme highs and lows that are felt by people who use heroin the highs and lows result from the waxing and waning of heroin levels in the blood.
Methadone has been used for more than 30 years to help patients overcome heroin addiction. If patients take methadone as prescribed, they are unlikely to get withdrawal symptoms when they stop taking heroin, or the withdrawal symptoms are much less severe.
Additionally, methadone blocks the high produced by heroin so that taking heroin is no longer rewarding. Patients on methadone remain physically dependent on the drug, but most of them no longer have the uncontrolled, compulsive, and disruptive behavior caused by heroin addiction.
In many studies over the past decade or so, researchers have tried to determine which methadone dosages work best to help patients overcome heroin addiction. That said, doctors in methadone clinics often see a wide range of dosages that are effective, and some of them treat patients with dosages that are lower or higher than the recommended amount.
In this study, the researchers examined the range of methadone dosages that helped patients achieve heroin abstinence. They also wanted to find factors that influenced whether a particular patient needed a higher or a lower dosage.
They studied heroin-addicted volunteers who started methadone treatment and followed them for a year. Of these, only achieved at least one month of heroin abstinence. The range of effective methadone dosages among the patients who achieved abstinence was very wide, from 1.
On the other hand, almost half of the patients who did not achieve heroin abstinence received the recommended dosage of 60 mg or more methadone. Overall, patients at clinics that generally adhered to the treatment guidelines and treated most patients at 60 mg or higher were more likely to achieve abstinence. Among patients who achieved abstinence, higher methadone doses were correlated with posttraumatic stress disorder, depression, a higher number of previous detoxifications from heroin, and some other factors.
This study confirms that effective methadone doses as defined by heroin abstinence for at least a month vary very widely. It shows that even high dosages that work for one patient may be too low for another patient and that a substantial fraction of patients achieve abstinence on less than the recommended dosage. The results also suggest that there are some factors that might predict whether a patient is more likely to need a higher dosage, such as a diagnosis of posttraumatic stress disorder or depression.
Most surprisingly, the results suggest that attempts to stop using methadone may actually increase the need for methadone over the long term. It seems therefore reasonable that doctors monitor the effects of treatment in each individual patient to find the most effective dose for that individual. However, as patients in clinics that adhere to the guidelines do better on average, the recommended dose should serve as a benchmark that might be adjusted upward or downward. Methods and Findings A volunteer sample of opioid-dependent US veterans initiating methadone treatment was prospectively observed over the year after treatment entry.
Conclusions Effective and ineffective methadone dosages overlap substantially. Hall, University of Queensland, Australia Received: May 13, ; Accepted: December 8, ; Published: February 7, This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
Introduction Methadone maintenance is one of the most highly researched and evidence-based treatments for illicit drug dependence. Methods Recruitment Patients were recruited through opioid substitution treatment programs located in eight cities throughout the United States. Data Analysis To examine effective versus actual dosing practices, cumulative dosage histograms were created for 1 the subpopulation that had at least 1 mo abstinence from heroin, 2 the subpopulation that never had a month of abstinence from heroin, 3 the subpopulation that attended a clinic with high guideline adherence, 4 the subpopulation that attended a clinic with lower guideline adherence.
Results Description of Effective and Actual Dosing Practices One hundred sixty-eight patients had at least 1 mo of abstinence from heroin. Download: PPT. Figure 1. Correlations between Patient Factors and Methadone Tolerance To determine factors associated with tolerance to the effects of methadone on heroin use, we examined whether quantity and frequency of drug use, experience of opiate withdrawal, family history of substance abuse, disease states, or treatment delivery factors were correlated with the dosage of methadone at which patients achieved heroin abstinence Table 1.
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