The amount of heroin used per day was estimated from self-reported pretreatment monthly cost of drug use, using average heroin price and purity data from the year of the study for each locality [ 27 ] and correcting for route of administration [ 28 ]. 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.
A multivariate linear regression model assessed factors that were associated with the dosage at which a patient abstained, controlling for multiple predictors simultaneously. One hundred sixty-eight patients had at least 1 mo of abstinence from heroin. Effective methadone dosages ranged from 1. Of patients who did not achieve abstinence, Mean daily dosages of methadone for patients in treatment ranged from 30 to mg median: Mean daily dosages received by patients who did not abstain from heroin use and mean daily dosages at low guideline-adherent sites were left-shifted on the cumulative dosage histogram as compared to effective dosages, suggesting that these patients were being dosed lower than necessary.
This difference was particularly pronounced in the higher dosage ranges. In contrast, dosages at high guideline-adherent sites were right-shifted as compared to effective dosing, suggesting that patients were receiving just slightly higher dosages than those given to patients who achieved abstinence. This variation from effective dosing practices is consistent with heroin use outcomes observed at high versus low guideline-adherent sites.
Patients who attended high guideline-adherent clinics had significantly lower rates of heroin use at follow-up [ 24 ]. 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.
Recent frequency of heroin use, the number of years that heroin had been used, and estimates of the amount of heroin used per day were not associated with effective methadone dosing levels. Higher local purity of heroin was associated with lower effective methadone dosage; this association was the opposite of common predictions.
Brief periods of withdrawal from opioids increase opioid tolerance in basic science studies [ 12 , 13 ]. We expect that opioid detoxification treatments constitute a significant percentage of the major withdrawal episodes that patients have experienced. We found that the number of previous drug detoxification treatments experienced tended to correlate with the dosage of methadone needed to abstain from heroin.
As expected, the number of previous ethanol detoxification treatments was not correlated with the effective methadone dosage. Although we do not have any measure of opioid tolerance in family members, this study did collect patient-reported data on family history of drug and alcohol problems.
Having a parent with a drug or alcohol problem was not associated with the effective methadone dosage. Chronic pain states, such as neuropathy, have been associated with analgesic tolerance to opioid medications [ 15 , 16 ]. To determine if chronic pain conditions increase tolerance to methadone's ability to prevent heroin use, we examined the association between reported pain levels and diagnoses of chronic pain conditions and effective methadone dosage. The severity of pain experienced in the past 4 wk or having a diagnosis of a chronic pain condition was not correlated with the effective dosage of methadone.
Having a recent diagnosis of PTSD was strongly correlated to the effective methadone dosage. This association did not hold for other anxiety disorders. Similarly, a recent or lifetime history of emotional, physical, or sexual abuse was not related to methadone tolerance, suggesting that methadone tolerance was related to PTSD, not trauma experience.
We examined whether depressive symptomatology or diagnosis was related to methadone dosing needs. Self-reported depression in the past 30 d and having a recent diagnosis of clinical depression correlated positively with effective dosage. However, self-reported depression experienced throughout the lifetime was not correlated with effective methadone dosage.
As a control, we examined whether mental health disorders for which specific opioid contributions have not been implicated were related to effective methadone dosage. Schizophrenia was not significantly correlated with effective dosage of methadone. Patients attending clinics designated as high guideline-adherent by the MOST study maintained abstinence on higher dosages of methadone high: To identify specific treatment factors contributing to this correlation, we examined the relationship of effective dosage with length of treatment, number of counseling visits, satisfaction with treatment, and the tendency of a clinic's counselors to encourage abstinent patients to reduce or eliminate their dosage of methadone.
Patients who stayed in treatment longer, received more counseling visits, and attended clinics where counselors did not encourage dose reduction received higher methadone dosages during periods of abstinence Table 1. To determine the predictive value of the above factors, patient variables significantly associated with methadone dosage were included in a multivariate linear regression model with effective methadone dosage as the dependent variable.
Because the study examined patient outcomes from sites specifically chosen for their differences in treatment practices, a variable encoding whether the patient attended a high or low guideline-adherent treatment clinic was included in the model. To assess which aspects of guideline adherence were related to effective methadone dosing, we replaced the variable encoding guideline-adherence rate with treatment-level variables found to correlate with effective dosage.
The patients who remained in methadone maintenance treatment for a longer period of time and attended clinics where counselors reported not favoring dosage reductions in abstinent patients received higher effective methadone dosages.
Having a diagnosis of PTSD increased effective methadone dosage by A diagnosis of depression also increased effective methadone dosage by Each previous drug detoxification episode increased the dosage of methadone at which patients abstained from heroin by 0.
Patients who were abstinent from heroin received 0. For each point change on the counselor's tendency to encourage dosage reduction scale, patients received 7. In total, these six variables accounted for Adding common predictive variables to the model did not alter the overall findings of the above model. Individual patients' opioid substitution medication needs vary greatly, a fact that is often overlooked in treatment research.
The dosages typically tested in randomized trials of methadone maintenance to date are below the dosage needed to achieve abstinence in patients at the high end of the dose response curve [ 1 , 3 , 4 , 6 ]. Thus, higher dosage conditions in trials almost always produce better outcomes on average than do lower dosage conditions.
The cumulative dose-response curve lends credence to clinicians' insistence that methadone dosing guidelines do not apply to all patients. Nevertheless, the importance of adequate dosing is obvious, as the slight leftward shift of the methadone dosage histogram in low guideline-adherent sites was associated with significantly greater heroin use among patients.
Dosage titration utilizing drug screening to measure dosage effectiveness should facilitate the determination of appropriate dosages for individual patients. Our analysis of factors related to opioid tolerance can inform clinicians' predictions of individual patients' methadone needs. First, these results suggest several possibly counterintuitive practices relating to patients' opioid use history. Although it may seem logical to expect patients who used lesser amounts or less pure heroin to need lower dosages of methadone, this expectation is not supported by our data.
The amount of heroin used per day did not predict effective methadone dosage, and living in an area with lower average local heroin purity predicted need for higher methadone dosages. It cannot be assumed that patients who became dependent using lower dosages of heroin will need lower dosages of methadone to achieve abstinence.
Ibuki et al. This theory predicts the counterintuitive result identified here that repeated opioid detoxifications increase tolerance to opioids. 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. The authors conclude that high-dose methadone leads to a significantly greater decline in opioid use. The decrease in opioid use in both groups was clinically significant, however. The authors note that daily dosages of more than mg may be required for optimal benefit in some patients, but current federal regulations discourage such a high dosage.
Already a member or subscriber? Log in. Interested in AAFP membership? Learn more. Strain EC, et al. Moderate- vs high-dose methadone in the treatment of opioid dependence.
A randomized trial. March 17, ;—5. This content is owned by the AAFP. A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference.
This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP. Contact afpserv aafp. Read the Issue. Methadone can cause serious unwanted effects if taken by adults who are not used to strong narcotic pain medicines, children, or pets. Make sure you store the medicine in a safe and secure place to prevent others from getting it.
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