Other findings of the study are also consistent with prior literature, including higher dose related to longer retention, use of other drugs associated with lower retention, and opiate use during treatment negatively related to dose for both groups. The unique contribution of the present study is that these findings were confirmed with this randomized trial conducted in community treatment programs in the U.S.First, approximately 25% of the BUP participants dropped out within first 30 days of treatment, suggesting a critical period calling for special efforts in retaining these participants. Second, of those who remained in treatment, positive opiate urine results were significantly lower among BUP relative to MET participants during the first 9 weeks of treatment. This finding confirms the advantage of BUP requiring a much shorter time for induction than MET. Third, there was a linear positive relationship between BUP dose and the treatment completion rate, suggesting the benefit of dosing greater than the common practice of a maximum dose of 16mg. However, even with the highest BUP dose level of 30–32mg allowed in this trial, the retention rate was less than the rate in the MET group , and approximately 30% of the participants continued opioid use. Besides additional strategies focusing on retaining BUP participants beyond 30 days of treatment, these findings suggest that participants may yet fare better with BUP doses higher than the 32mg used in this study. Given the generally high safety profile of BUP and the lack of any significant side effects and other adverse effects at the high dose range observed in this study, we believe with proper monitoring safety will not be a clinical concern in such an effort.Finally, the study has identified additional participant characteristics predicting dropout, including being young, Hispanic, and concomitant use of heroin or other drugs such as cannabinoids,grow cannabis cocaine or amphetamine during treatment. Treatment programs may consider paying special attention to patients with these characteristics to prevent dropout. It should be noted that our finding on cannabinoids is in contrast to most prior studies that have found no effect of the use of cannabis on methadone treatment outcomes including treatment retention.
A potential explanation for this discrepancy may be that strains of marijuana available more recently, when the current study was conducted, have been deliberately bred to have high concentrations of delta-9-tetrahydrocannabinol making them much more potent and potentially more destabilizing for patients on opioid maintenance therapy. The study has several limitations. There were limited measures of participant motivation and program and community characteristics that are likely to influence treatment retention. Reasons for dropout were coarsely recorded; although the data did indicate that many more BUP participants simply discontinued their treatment. A qualitative study of this sample has suggested that BUP participants reported negative physical reactions or did not like BUP,being previously familiar with MET, and thus dropped out.The findings must also be taken in the context of an open-label, unblinded clinical trial. Despite these limitations, the study revealed several important findings as discussed earlier. Given the linear trend of higher BUP dose related to increased retention, future studies should investigate if BUP doses greater than 32mg should be considered to increase retention, and perhaps to further reduce opioid use during treatment. One study which examined BUP doses of 24–56mg/d among 650 patients showed a retention rate over 92% at 30 months and, similar to the present investigation, decreasing rates of illicit substance use at the higher doses.In research or clinical practice, BUP is often prescribed at a dose of 16mg or lower, as BUP is an opioid partial agonist with a ‘ceiling effect’ for respiratory depression and in previous human laboratory studies, higher doses of BUP revealed a flattening out of the dose-effect curve, i.e. increasing doses do not result in greater changes in subjective measures or respiratory rate.A recent review article indicates that the risk of respiratory depression associated with BUP is lower than with other opioids including methadone.It appears that the current common practice of prescribing at a dose of 16mg per day and not to exceed 32mg maximum is driven by the ceiling effect observed and a few PET scan studies showing high mu receptor occupancy as well as concerns about diversion.However, these studies were based on small samples and do not take into account inter-individual variation and the other potential non-mu effects of BUP.
History has taught that for about 20 years it was common to have MET dose ceilings of 40mg per day, but it is now well established that this is inadequate to maintain the necessary plasma concentrations to be effective; the effective range is between 60mg and 120mg or higher per day for most patients.The current study suggests the possibility of BUP at a dose of 32mg or higher having a potential impact on improving treatment retention and outcome. Thus, further investigations of the safety, efficacy, and clinical utilities of higher doses of BUP should be considered. The high dropout rates at the early phase of BUP treatment suggest the need for early interventions to prevent dropout. It is possible that more intensive psychosocial support could help, although studies to date indicate little benefit to increased counseling for patients treated with buprenorphine.An alternative approach as propounded by Kakko et al. and demonstrated efficacious in a randomized trial is prompt, early transfer to MET of patients who do not quickly stabilize on BUP.A more widespread introduction of contingency management into opioid treatment programs could also help to optimize retention and outcomes for both BUP and MET.Finally, heroin-assisted treatment is used in several European countries with success, particularly for people with opioid dependence who continue intravenous heroin while on methadone maintenance or who are not enrolled in treatment.BUP retention may also be improved with take-home doses as permitted by regulation and as standard in office-based practice supervised by physicians, which obviates the need for daily attendance in clinic for dosing. As described earlier, the trial was conducted among community methadone maintenance programs and thus may not be optimal for delivering BUP treatment. The nine clinics were all federally licensed opioid treatment programs that have provided treatment with methadone for many years. All staff and most participants had previous experience with MET, and participants came to these programs for methadone treatment. Because BUP was delivered within these methadone maintenance programs, all programs delivered BUP following the same rules and regulations for methadone prescription ,indoor cannabis grow system precluding the flexibility and individualization possible in office-based treatment that may help to retain some patients.The differential retention of males by medication condition has no definitive explanation and deserves future investigation. Since opioids suppress the hypothalamic-pituitary-gonadal axis leading to lower testosterone levels, it may be that BUP, as a partial agonist, does so less than MET, and thus males find BUP more tolerable in that regard.
In conclusion, the study findings suggest the need to investigate the use of higher medication doses, particularly for BUP, address continued use of opiate and other drugs such as cocaine, amphetamines, and cannabinoids, and further study and identify factors/ strategies influencing BUP retention, particularly during the first 30 days of treatment in order to help in efforts to improve engagement and retention in opioid treatment programs.The cannabinoid system has an important impact on liver-related fibrosis, steatosis, regeneration, and portal hypertension. Endocannabinoid ligands are ubiquitous and interact with cannabinoid receptors 1 and 2, which have high affinity for tetrahydrocannabinol , the psychoactive mediator of marijuana. Under physiologic conditions, hepatic expression of CB1 and CB2 is weak or absent. However, both receptors are up-regulated in a variety of liver diseases, including alcoholic and nonalcoholic liver disease, liver fibrosis, chronic hepatitis C, primary biliary cirrhosis, and hepatocellular carcinoma. Limited studies have examined the impact of THC use and liver fibrosis progression, with conflicting results. Some cross sectional studies have shown evidence of increased fibrosis, and other longitudinal studies of relatively short duration suggest no impact on fibrosis progression. Data are lacking on the influence of long-term THC use on liver-related outcomes such as fibrosis in human immunodeficiency virus /hepatitis C virus –coinfected individuals. For this reason, we sought to examine the impact of THC use on liver fibrosis progression in a well-characterized cohort of women coinfected with HIV and HCV.The Women’s Interagency HIV Study is a prospective, multi-center, longitudinal observational cohort of adult women infected with HIV or at high risk of acquiring HIV, described in detail elsewhere. Approximately 30% of HIV-infected women enrolled were coinfected with HCV prior to enrollment in WIHS. A total of 4137 women have been enrolled in the first 3 enrollment cohorts . All women gave informed consent at entry, and the study was approved by each center’s institutional review board. Patients are seen in follow-up every 6 months, where detailed sociodemographic, medical, and behavioral data are collected through structured interviews, physical examination, and biologic specimen collection. As of visit 37 , a total of 790 women with HIV/HCV coinfection at baseline had enrolled in the WIHS into cohorts 1 and 2, and were included in our analysis. HIV infection was confirmed by positive HIV enzyme-linked immunosorbent assay and a confirmatory Western blot, and HCV infection was defined as a positive result for serum HCV RNA at entry into the study. THC use is prevalent in the WIHS; 14% of participants regularly use marijuana, and 6% report daily use. Liver biopsy is not performed as part of the WIHS observational study. However, noninvasive markers of liver fibrosis, aspartate aminotransferase to platelet ratio index , and FIB-4 have been validated in this cohort.Sociodemographic data including age, ethnicity, race, and past substance use were collected at entry into WIHS. Biologic specimens were collected at visits every 6 months with testing for liver enzymes, renal function, complete blood count, CD4 count, and HIV RNA load. HIV RNA was measured using the isothermal nucleic acid sequence–based amplification method with a lower limit of detection of 80 copies/mL.
Highly active antiretroviral therapy was defined by the contemporaneous US Department of Health and Human Services guidelines. Second- or third-generation enzyme immunoassays were utilized for HCV antibody detection and confirmed by documenting HCV RNA seropositivity and by reverse transcription polymerase chain reaction . Hepatitis B was tested within the first year of enrollment and was defined as hepatitis B surface antigenemia. Data including body mass index, history of hypertension, diabetes, and insulin resistance were collected. Diabetes was defined as any fasting glucose measurement of >126 mg/dL, hemoglobin A1c measured at ≥6.5%, or self-report of taking antidiabetic medication.Discrete variables were summarized using frequency and percentages; continuous variables were summarized using mean and standard deviation for normally distributed data, and median and interquartile range for non-normally distributed data. Comparisons between THC use groups were made using the χ2 or Fisher exact tests for categorical data and analysis of variance or Kruskal–Wallis tests for continuous data. The cumulative probability of progression to advanced fibrosis was estimated using the Kaplan–Meier method and compared by THC use category with the log-rank test. All analyses were 2 tailed, with P < .05 considered statistically significant. Risk of progression to advanced fibrosis was evaluated separately for FIB-4 and APRI outcomes using Cox proportional hazards regression. Hazard ratios and 95% confidence intervals were calculated from the models. To account for the fact that patients must remain alive to enter the study, age at study entry was treated as a left-truncated variable with age used as the time scale. Patients were followed until their first visit with significant fibrosis or were censored at the date of last fibrosis measurement for those not progressing to the event. Factors with a univariable P < .1 and THC use were evaluated in the multi-variable model. The model was selected by backward elimination with P > .05 for removal from the model. The final model included 2 additional variables: biologically relevant HCV RNA and evaluate whether long-term THC exposure impacted fibrosis progression. We also conducted sub-analyses in participants with at least mild fibrosis to evaluate whether the presence of some fibrosis is a prerequisite for THC to modulate fibrosis progression. Data were analyzed using SAS software version 9.4 .