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1.  Methadone vs. buprenorphine/naloxone during early opioid substitution treatment: a naturalistic comparison of cognitive performance relative to healthy controls 
Background
Both methadone- and buprenorphine-treated opioid-dependent patients frequently show cognitive deficits in attention, working memory, and verbal memory. However, no study has compared these patient groups with each other during early opioid substitution treatment (OST). Therefore, we investigated attention, working memory, and verbal memory of opioid-dependent patients within six weeks after the introduction of OST in a naturalistic setting and compared to those of healthy controls.
Methods
The sample included 16 methadone-, 17 buprenorphine/naloxone-treated patients, and 17 healthy controls matched for sex and age. In both groups buprenorphine was the main opioid of abuse during the recent month. Benzodiazepine codependence, recent use, and comedication were also common in both patient groups. Analysis of variance was used to study the overall group effect in each cognitive test. Pair-wise group comparisons were made, when appropriate
Results
Methadone-treated patients, as a group, had significantly slower simple reaction time (RT) compared to buprenorphine/naloxone-treated patients. In Go/NoGo RT methadone patients were significantly slower than controls. Both patient groups were significantly debilitated compared to controls in working memory and verbal list learning. Only methadone patients were inferior to controls in story recall. In simple RT and delayed story recall buprenorphine/naloxone patients with current benzodiazepine medication (n = 13) were superior to methadone patients with current benzodiazepine medication (n = 13). When methadone patients were divided into two groups according to their mean dose, the patient group with a low dose (mean 40 mg, n = 8) showed significantly faster simple RT than the high dose group (mean 67 mg, n = 8).
Conclusion
Deficits in attention may only be present in methadone-treated early phase OST patients and may be dose-dependent. Working memory deficit is common in both patient groups. Verbal memory deficit may be more pronounced in methadone-treated patients than in buprenorphine/naloxone-treated patients. In sum, to preserve cognitive function in early OST, the use of buprenorphine/naloxone may be more preferable to methadone use of, at least if buprenorphine has been recently abused and when benzodiazepine comedication is used. Longitudinal studies are needed to investigate if the better performance of buprenorphine/naloxone-treated patients is a relatively permanent effect or reflects "only" transient opioid switching effect.
doi:10.1186/1472-6904-7-5
PMCID: PMC1914339  PMID: 17565668
2.  Memory function in opioid-dependent patients treated with methadone or buprenorphine along with benzodiazepine: longitudinal change in comparison to healthy individuals 
Background
Opioid-substitution treatment (OST) for opioid dependence (OD) has proven effective in retaining patients in treatment and reducing illegal opiate abuse and crime. Consequently, the World Health Organization (WHO) has listed the opioid agonists methadone and buprenorphine as essential drugs for OD that should be available worldwide. In many areas of the world, OD is often associated with concomitant benzodiazepine (BZD) dependence and abuse, which complicates treatment. However, possible changes in the cognitive functioning of these patients are not well-known. The present study is the first to examine longitudinal stability of memory function in OST patients with BZD use, thus providing a new tool for health policy authorities in evaluating the usefulness of OST.
Methods
Within the first two months (T1) and between 6–9 months (T2) after OST admission, we followed the working memory, immediate verbal memory, and memory consolidation of 13 methadone- and 15 buprenorphine- or buprenorphine/naloxone-treated patients with BZD dependence or abuse disorder. The results were compared to those of fifteen normal comparison participants. All participants also completed a self-reported memory complaint questionnaire on both occasions.
Results
Both patient groups performed statistically significantly worse than normal comparison participants in working memory at time points T1 and T2. In immediate verbal memory, as measured by list learning at T1, patients scored lower than normal comparison participants. Both patient groups reported significantly more subjective memory problems than normal comparison participants. Patients with more memory complaints recalled fewer items at T2 from the verbal list they had learned at T1 than those patients with fewer memory complaints. The significance of the main analyses remained nearly the same when the statistical tests were performed without buprenorphine-only patients leaving 12 patients to buprenorphine/naloxone group.
Conclusion
Working memory may be persistently affected in OST patients with BZD use. A high number of memory complaints among OST patients with BZD use may indicate memory consolidation impairment. These findings show that recovery of memory function in OD patients treated along with BZDs takes time, and their memory complaints may have practical relevance.
doi:10.1186/1747-597X-4-6
PMCID: PMC2676265  PMID: 19374740
3.  Do drug treatment variables predict cognitive performance in multidrug-treated opioid-dependent patients? A regression analysis study 
Background
Cognitive deficits and multiple psychoactive drug regimens are both common in patients treated for opioid-dependence. Therefore, we examined whether the cognitive performance of patients in opioid-substitution treatment (OST) is associated with their drug treatment variables.
Methods
Opioid-dependent patients (N = 104) who were treated either with buprenorphine or methadone (n = 52 in both groups) were given attention, working memory, verbal, and visual memory tests after they had been a minimum of six months in treatment. Group-wise results were analysed by analysis of variance. Predictors of cognitive performance were examined by hierarchical regression analysis.
Results
Buprenorphine-treated patients performed statistically significantly better in a simple reaction time test than methadone-treated ones. No other significant differences between groups in cognitive performance were found. In each OST drug group, approximately 10% of the attention performance could be predicted by drug treatment variables. Use of benzodiazepine medication predicted about 10% of performance variance in working memory. Treatment with more than one other psychoactive drug (than opioid or BZD) and frequent substance abuse during the past month predicted about 20% of verbal memory performance.
Conclusions
Although this study does not prove a causal relationship between multiple prescription drug use and poor cognitive functioning, the results are relevant for psychosocial recovery, vocational rehabilitation, and psychological treatment of OST patients. Especially for patients with BZD treatment, other treatment options should be actively sought.
doi:10.1186/1747-597X-7-45
PMCID: PMC3551729  PMID: 23121989
Opioid-dependence; Opioid agonist therapy; Pharmacotherapy; Psychotropic drugs; Neurocognitive performance; Neuropsychological testing
4.  A Web-Based Behavior Therapy Program Influences the Association Between Cognitive Functioning and Retention and Abstinence in Clients Receiving Methadone Maintenance Treatment 
Journal of dual diagnosis  2012;8(4):283-293.
Objective
Deficits in cognitive functioning have been well-documented in persons with substance use disorders. In addition, some evidence suggests that poorer cognitive functioning predicts poorer engagement in substance abuse treatment and worse treatment outcomes.
TRIAL DESIGN
Non-blind, randomized clinical trial with parallel design.
Methods
Clients were recruited from a local methadone maintenance clinic within the first 30 days of treatment. All participants completed a comprehensive, computerized neuropsychological assessment (MicroCog) at the time they entered the clinical trial. Participants were randomized to receive 12 months of either standard methadone maintenance treatment, or methadone maintenance treatment with an integrated web-based intervention as part of treatment. The aims of the current study were to (1) characterize the cognitive functioning of clients entering methadone maintenance treatment; (2) evaluate the impact of cognitive functioning on the primary outcomes of treatment retention and opioid abstinence; and (3) determine whether cognitive functioning had a differential impact on these outcomes across treatment conditions. Randomization was non-blind and participants were stratified on past month cocaine use, prior history of methadone, LAAM or buprenorphine treatment, and counselor.
Results
Eighty participants were randomized to each condition (total n=160). Mean scores on MicroCog scales fell in the average and low average ranges and there were no differences in scores between treatment groups. Lower scores on General Cognitive Proficiency predicted longer study retention (χ2=5.03, p < .05), though this effect was quite small. Generalized linear modeling showed that scores on all MicroCog scales except for Spatial Processing significantly predicted opioid abstinence (defined as percent of total weeks and percent of tested weeks with continuous abstinence), with lower scores predicting smaller percentages of continuous weeks of abstinence. This pattern was not evident in regression analyses in which abstinence was defined as number of total weeks of abstinence. An interaction effect was observed, whereby lower cognitive scores predicted lower levels of abstinence for participants in standard methadone maintenance treatment, but not for those who received the web-based intervention as part of methadone maintenance treatment.
Conclusions
Technology-based interventions may hold promise for minimizing the impact of poorer cognitive functioning on treatment outcomes.
doi:10.1080/15504263.2012.723317
PMCID: PMC3650891  PMID: 23671409
cognitive; methadone maintenance treatment; technology; web-based intervention
5.  Enhancement of tolerance development to morphine in rats prenatally exposed to morphine, methadone, and buprenorphine 
Background
Abuse of addictive substances is a serious problem that has a significant impact on areas such as health, the economy, and public safety. Heroin use among young women of reproductive age has drawn much attention around the world. However, there is a lack of information on effects of prenatal exposure to opioids on their offspring. In this study, an animal model was established to study effects of prenatal exposure to opioids on offspring.
Methods
Female pregnant Sprague-Dawley rats were sub-grouped to receive (1) vehicle, (2) 2-4 mg/kg morphine (1 mg/kg increment per week), (3) 7 mg/kg methadone, and (4) 3 mg/kg buprenorphine, subcutaneously, once or twice a day from E3 to E20. The experiments were conducted on animals 8-12 weeks old and with body weight between 250 and 350 g.
Results
Results showed that prenatal exposure to buprenorphine caused higher mortality than other tested substance groups. Although we observed a significantly lower increase in body weight in all of the opioid-administered dams, the birth weight of the offspring was not altered in all treated groups. Moreover, no obvious behavioral abnormality or body-weight difference was noted during the growing period (8-12 weeks) in all offspring. When the male offspring received morphine injection twice a day for 4 days, the prenatally opioid-exposed rats more quickly developed a tolerance to morphine (as shown by the tail-flick tests), most notably the prenatally buprenorphine-exposed offspring. However, the tolerance development to methadone or buprenorphine was not different in offspring exposed prenatally to methadone or buprenorphine, respectively, when compared with that of the vehicle controlled group. Similar results were also obtained in the female animals.
Conclusions
Animals prenatally exposed to morphine, methadone, or buprenorphine developed tolerance to morphine faster than their controlled mates. In our animal model, prenatal exposure to buprenorphine also resulted in higher mortality and much less sensitivity to morphine-induced antinociception than prenatal exposure to morphine or methadone. This indicates that buprenorphine in higher doses may not be an ideal maintenance drug for treating pregnant women. This study provides a reference in selecting doses for clinical usage in treating pregnant heroin addicts.
doi:10.1186/1423-0127-17-46
PMCID: PMC2890660  PMID: 20529288
6.  Neuropsychological functioning in opiate-dependent subjects receiving and following methadone maintenance treatment 
Drug and alcohol dependence  2006;84(3):240-247.
Objective
An accumulating body of research suggests that former heroin abusers in methadone maintenance therapy (MMT) exhibit deficits in cognitive function. Whether these deficits are present in former methadone maintained patients following discontinuation of MMT is unknown. This study tests the hypothesis that former heroin users who have detoxified from methadone maintenance therapy and are drug-free have less pronounced cognitive impairment than patients continuing long-term MMT.
Method
A series of neuropsychological tests were administered to three groups of subjects: 29 former heroin addicts receiving methadone maintenance treatment, 27 former heroin addicts withdrawn from all opiates, and 29 healthy controls without a history of drug dependence. Testing included Wechsler Adult Intelligence Scale-Revised Vocabulary Test, the Stroop Color-Word Test, the Controlled Oral Word Association Test, the Benton Visual Retention Test, and a Substance Use Inventory.
Findings
Both methadone-maintained and abstinent subject groups performed worse than controls on tasks that measured verbal function, visual-spatial analysis and memory, and resistance to distractibility. Abstinent subjects performed worse than their methadone maintained counterparts on tests measuring visual memory and construct formation. Cognitive impairment did not correlate with any index of drug use.
Conclusions
We confirmed previous findings of neuropsychological impairment in long-term MMT recipients. Both patients receiving MMT and former heroin users in prolonged abstinence exhibited a similar degree of cognitive impairment. Cognitive dysfunction in patients receiving methadone maintenance may not resolve following methadone detoxification.
doi:10.1016/j.drugalcdep.2006.02.006
PMCID: PMC2067988  PMID: 16545923
Methadone; Opiates; Dependence; Abstinence; Neuropsychological; Cognitive
7.  Patient Perspectives on Choosing Buprenorphine over Methadone in an Urban Equal Access System 
Background
Recent policy initiatives in Baltimore City, MD significantly reduced access disparities between methadone and buprenorphine in the publicly-funded treatment sector.
Objectives
This study examines reasons for choosing buprenorphine over methadone among patients with access to both medications.
Methods
This study was embedded within a larger clinical trial conducted at two outpatient substance abuse treatment programs offering buprenorphine. Qualitative and quantitative data on treatment choice were collected for new patients starting buprenorphine treatment (n=80). The sample consisted of predominantly urban African American (94%) heroin users who had prior experience with non-prescribed street buprenorphine (85%) and opioid agonist treatment (68%). Qualitative data were transcribed and coded for themes, while quantitative data were analyzed using descriptive and bivariate statistics.
Results
Participants typically conveyed their choice of buprenorphine treatment as a decision against methadone. Buprenorphine was perceived as a helpful medication while methadone was perceived as a harmful narcotic with multiple unwanted physical effects. Positive experiences with non-prescribed “street buprenorphine” were a central factor in participants’ decisions to seek buprenorphine treatment.
Conclusions
Differences in service structure between methadone and buprenorphine did not strongly influence treatment-seeking decisions in this sample. Personal experiences with medications and the street narrative surrounding them play an important role in treatment selection decisions.
Scientific Significance
This study characterizes important decision factors that underlie patients’ selection of buprenorphine over methadone treatment.
doi:10.1111/j.1521-0391.2012.12004.x
PMCID: PMC4215541  PMID: 23617873
buprenorphine; methadone; treatment choice; diversion; street narrative; patient perspective
8.  Comparison of pain models to detect opioid-induced hyperalgesia 
Journal of Pain Research  2012;5:99-106.
Objective
Chronic opioid therapy may be associated with hyperalgesia. Our objective was to determine if opioid-induced hyperalgesia detection sensitivity is dependent on the stimulus used to detect it.
Methods
This open design study compared the detection of hyperalgesia in opioid-dependent subjects (n = 16) and healthy control subjects (n = 16) using the following pain stimuli: cold pain, electrical stimulation, mechanical pressure, and ischemic pain. The opioid-dependent subjects were maintained on either methadone (n = 8) or buprenorphine (n = 8) for at least 3 months. None of the controls was dependent on opioids or other drugs of abuse.
Results
The opioid-dependent subjects were markedly more sensitive than controls to the cold pain test. Compared with the control group, the hazard ratio for ceasing the test due to intolerable pain was 7.7 (95% confidence interval [CI] 2.6–23.3) in the buprenorphine group and 4.5 (95% CI 1.7–15.6) in the methadone group, with similar data for the cold pain threshold. Of the remaining tests, there were differences only for the electrical pain threshold between treatment groups, with the geometric mean threshold in the buprenorphine group being 1.5 (95% CI 1.1–1.9)-fold higher (ie, less sensitive) than that of the controls; the geometric mean for the methadone group was 1.3 (95% CI 1.04–1.7)-fold higher than that of the controls. There were no significant differences between buprenorphine and methadone patients in test responses. Women were more sensitive to the cold pain (hazard ratio for tolerance, 3.1 [95% CI 1.4–7.3]) and ischemic tests (hazard ratio for tolerance, 2.7 [95% CI 1.2–6.1]). There were significant correlations between cold and ischemic tolerances (r = 0.50; P = 0.003) and between electrical and mechanical pain tolerances (r = 0.52; P = 0.002).
Conclusion
These findings indicate that cold pain is the most suitable of the methods tested to detect opioid-induced hyperalgesia. This is consistent with its sensitivity to detect opioid analgesia.
doi:10.2147/JPR.S27738
PMCID: PMC3346067  PMID: 22570562
opioid-induced hyperalgesia; opioid-dependent subjects; pain models
9.  Comparing methadone and buprenorphine maintenance with methadone-assisted withdrawal for the treatment of opioid dependence during pregnancy: maternal and neonatal outcomes 
Substance Abuse and Rehabilitation  2012;3(Suppl 1):17-25.
Pregnancy can motivate opioid-dependent women to seek substance abuse treatment. Research has demonstrated that although prenatal exposure to buprenorphine results in less severe neonatal abstinence syndrome (NAS) relative to prenatal methadone exposure, the maternal and other neonatal outcomes are similar for the two medications. Maternal and neonatal outcomes for opioid-dependent pregnant women receiving these medications have not been systematically ompared with methadone-assisted withdrawal. The present study provides an initial assessment of the relative efficacy of both methadone and buprenorphine maintenance versus methadone-assisted withdrawal in terms of neonatal and maternal delivery outcomes. Data were derived from (1) the MOTHER (Maternal Opioid Treatment: Human Experimental Research) study at the Johns Hopkins University Bayview Medical Center (JHBMC), or (2) retrospective records review of women who underwent methadone-assisted withdrawal at the JHBMC during the time period in which participants were enrolled in the MOTHER study. Compared with the methadone maintenance group, the methadone-assisted withdrawal group had a significantly lower mean NAS peak score (Means = 13.7 vs 7.0; P = 0.002), required a significantly lower mean amount of morphine to treat NAS (Means = 82.8 vs 0.2; P < 0.001), had significantly fewer days medicated for NAS (Means = 31.5 vs 3.9; P < 0.001), and remained in the hospital for a significantly fewer number of days, on average (Means = 24.2 vs 7.0; P < 0.019). Compared with the buprenorphine maintenance group, the methadone-assisted withdrawal group required a significantly lower mean amount of morphine to treat NAS (Means = 8.2 vs 0.2; P < 0.001) and significantly fewer days medicated for NAS (Means = 12.0 vs 3.9; P = 0.008). Findings suggest that it is possible for some opioid-dependent pregnant women to succeed with methadone-assisted withdrawal. Future research needs to more fully evaluate the potential benefits and risks of methadone-assisted withdrawal for the maternal-fetal dyad.
doi:10.2147/SAR.S26288
PMCID: PMC3889178  PMID: 24474873
pregnancy; methadone; buprenorphine; detoxification; women; neonates
10.  Methadone Induction in Primary Care for Opioid Dependence: A Pragmatic Randomized Trial (ANRS Methaville) 
PLoS ONE  2014;9(11):e112328.
Objective
Methadone coverage is poor in many countries due in part to methadone induction being possible only in specialized care (SC). This multicenter pragmatic trial compared the effectiveness of methadone treatment between two induction models: primary care (PC) and SC.
Methods
In this study, registered at ClinicalTrials.Gov (NCT00657397), opioid-dependent individuals not on methadone treatment for at least one month or receiving buprenorphine but needing to switch were randomly assigned to start methadone in PC (N = 155) or in SC (N = 66) in 10 sites in France. Visits were scheduled at months M0, M3, M6 and M12. The primary outcome was self-reported abstinence from street-opioids at 12 months (M12) (with an underlying 15% non-inferiority hypothesis for PC). Secondary outcomes were abstinence during follow-up, engagement in treatment (i.e. completing the induction period), retention and satisfaction with the explanations provided by the physician. Primary analysis used intention to treat (ITT). Mixed models and the log-rank test were used to assess the arm effect (PC vs. SC) on the course of abstinence and retention, respectively.
Results
In the ITT analysis (n = 155 in PC, 66 in SC), which compared the proportions of street-opioid abstinent participants, 85/155 (55%) and 22/66 (33%) of the participants were classified as street-opioid abstinent at M12 in PC and SC, respectively. This ITT analysis showed the non-inferiority of PC (21.5 [7.7; 35.3]). Engagement in treatment and satisfaction with the explanations provided by the physician were significantly higher in PC than SC. Retention in methadone and abstinence during follow-up were comparable in both arms (p = 0.47, p = 0.39, respectively).
Conclusions
Under appropriate conditions, methadone induction in primary care is feasible and acceptable to both physicians and patients. It is as effective as induction in specialized care in reducing street-opioid use and ensuring engagement and retention in treatment for opioid dependence.
Trial registration
Number Eudract 2008-001338-28; ClinicalTrials.gov: NCT00657397; International Standard Randomized Controlled Trial Number Register ISRCTN31125511
doi:10.1371/journal.pone.0112328
PMCID: PMC4231094  PMID: 25393311
11.  Randomized Controlled Trials in Pregnancy: Scientific and Ethical Aspects Exposure to different opioid medications during pregnancy in an intra-individual comparison 
Addiction (Abingdon, England)  2011;106(7):1355-1362.
Background
Chronic medical conditions such as opioid dependence require evidence-based treatment recommendations. However, pregnant women are underrepresented in clinical trials. We describe the first within-subject comparison of maternal and neonatal outcomes for methadone vs. buprenorphine exposed pregnancies. Though methadone is the established treatment of pregnant opioid dependent women, recent investigations have shown a trend for a milder neonatal abstinence syndrome (NAS) under buprenorphine. However, it is not only the choice of maintenance medication that determines the occurrence of NAS, other factors such as maternal metabolism, illicit substance abuse and nicotine consumption also influence its severity and duration and represent confounding factors in the assessment of randomized clinical trials.
Case series description
Three women who were part of the European cohort of a randomized, double-blind multicenter trial with a contingency management tool [the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study], each had two consecutive pregnancies and were maintained on either methadone or buprenorphine for their first and then the respective opposite, still-blinded medication for their second pregnancy. Birth measurements, the total neonatal abstinence score, the total amounts of medication used to treat NAS and the days of NAS treatment duration were assessed.
Results
Both medications were effective and safe in reducing illicit opioid relapse and avoiding preterm labour. Methadone maintenance yielded to a significantly higher neonatal birth weight. Data patterns suggest that buprenorphine-exposure was associated with lower neonatal abstinence syndrome (NAS) scores. Findings from this unique case series are consistent with earlier reports using between-group analyses.
Conclusions
Buprenorphine has the potential to become an established treatment alternative to methadone for pregnant opioid dependent women. Under special consideration of ethical boundaries, psychopharmacological treatment during pregnancy must be addressed as an integral part of clinical research projects in order to optimize treatment for women and neonates.
doi:10.1111/j.1360-0443.2011.03440.x
PMCID: PMC3107876  PMID: 21438938
opioid dependence; methadone; buprenorphine; pregnancy; neonatal abstinence syndrome
12.  Opioid Addiction and Abuse in Primary Care Practice: A Comparison of Methadone and Buprenorphine as Treatment Options 
Opioid abuse and addiction have increased in frequency in the United States over the past 20 years. In 2009, an estimated 5.3 million persons used opioid medications nonmedically within the past month, 200 000 used heroin, and approximately 9.6% of African Americans used an illicit drug. Racial and ethnic minorities experience disparities in availability and access to mental health care, including substance use disorders.
Primary care practitioners are often called upon to differentiate between appropriate, medically indicated opioid use in pain management vs inappropriate abuse or addiction. Racial and ethnic minority populations tend to favor primary care treatment settings over specialty mental health settings. Recent therapeutic advances allow patients requiring specialized treatment for opioid abuse and addiction to be managed in primary care settings. The Drug Addiction Treatment Act of 2000 enables qualified physicians with readily available short-term training to treat opioid-dependent patients with buprenorphine in an office-based setting, potentially making primary care physicians active partners in the diagnosis and treatment of opioid use disorders.
Methadone and buprenorphine are effective opioid replacement agents for maintenance and/or detoxification of opioid-addicted individuals. However, restrictive federal regulations and stigmatization of opioid addiction and treatment have limited the availability of methadone. The opioid partial agonist-antagonist buprenorphine/naloxone combination has proven an effective alternative. This article reviews the literature on differences between buprenorphine and methadone regarding availability, efficacy, safety, side-effects, and dosing, identifying resources for enhancing the effectiveness of medication-assisted recovery through coordination with behavioral/psychological counseling, embedded in the context of recovery-oriented systems of care.
PMCID: PMC4039205  PMID: 23092049
substance; abuse/use
13.  Maintenance Medication for Opiate Addiction: The Foundation of Recovery 
Journal of addictive diseases  2012;31(3):207-225.
Illicit use of opiates is the fastest growing substance use problem in the United States and the main reason for seeking addiction treatment services for illicit drug use throughout the world. It is associated with significant morbidity and mortality related to HIV, hepatitis C, and overdose. Treatment for opiate addiction requires long-term management. Behavioral interventions alone have extremely poor outcomes, with more than 80% of patients returning to drug use. Similarly poor results are seen with medication assisted detoxification. This article provides a topical review of the three medications approved by the FDA for long-term treatment of opiate dependence: the opioid agonist methadone, the opioid partial agonist buprenorphine, and the opioid antagonist naltrexone. Basic mechanisms of action and treatment outcomes are described for each medication. Results indicate that maintenance medication provides the best opportunity for patients to achieve recovery from opiate addiction. Extensive literature and systematic reviews show that maintenance treatment with either methadone or buprenorphine is associated with retention in treatment, reduction in illicit opiate use, decreased craving, and improved social function. Oral naltrexone is ineffective in treating opiate addiction but recent studies using extended release naltrexone injections have shown promise. While no direct comparisons between extended release naltrexone injections and either methadone or buprenorphine exist, indirect comparison of retention shows inferior outcome compared to methadone and buprenorphine. Further work is needed to compare directly each medication and determine individual factors that can assist in medication selection. Until such time, selection of medication should be based on informed choice following a discussion of outcomes, risks, and benefits of each medication.
doi:10.1080/10550887.2012.694598
PMCID: PMC3411273  PMID: 22873183
Review; opiate; addiction; methadone; buprenorphine; naltrexone; pharmacotherapy
14.  Management of Acute Postpartum Pain in Patients Maintained on Methadone or Buprenorphine During Pregnancy 
Background
Empirical evidence is needed to guide adequate post-partum pain relief of methadone and buprenorphine stabilized patients.
Objectives
To first determine the adequacy of pain control using non-opioid and opioid medication in participants stabilized on buprenorphine or methadone before a vaginal delivery. Second, to compare the amount of non-opioid and opioid medication needed for adequate pain control for buprenorphine-and methadone-maintained patients during the immediate post-partum period.
Methods
Pain control adequacy and amount of non-opioid and opioid medication needed in buprenorphine- (n=8) and methadone-maintained (n=10) patients over the first five days post-partum were examined.
Results
Pain ratings and number of opioid medication doses decreased over time in both medication groups. While the buprenorphine and methadone groups began with similar mean daily ibuprofen (IB) doses, the buprenorphine group decreased its IB use, while the methadone group increased its IB use.
Conclusions and Scientific Significance
Patients treated daily with either buprenorphine or methadone can have adequate pain control post-partum with opioid medication and IB. Pain control is dependent on the opioid-agonist medication in use at delivery, and must be individualized.
doi:10.1080/00952990902825413
PMCID: PMC2925397  PMID: 19462298
15.  Results of a Pilot Randomized Controlled Trial of Buprenorphine For Opioid Dependent Women in the Criminal Justice System 
Drug and alcohol dependence  2011;119(3):172-178.
Aims
Recent studies have demonstrated the efficacy of both methadone and buprenorphine when used with opioid dependent men transitioning from prison to the community, but no studies have been conducted with women in the criminal justice (CJ) system. The aim of this study was to determine the efficacy of buprenorphine for relapse prevention among opioid dependent women in the CJ system transitioning back to the community.
Methods
36 women under CJ supervision were recruited from an inpatient drug treatment facility that treats CJ individuals returning back to the community. Nine were enrolled in an open label buprenorphine arm then 27 were randomized to buprenorphine (n=15) or placebo (n=12; double-blind). All women completed baseline measures and started study medication prior to release. Participants were followed weekly, provided urine drug screens (UDS), received study medication for 12 weeks, and returned for a 3 month follow-up. Intent-to-treat analyses were performed for all time points through end-of-treatment (EOT).
Results
The majority of participants were Caucasian (88.9%), young (M±SD=31.8±8.4 years), divorced/separated (59.2%) women with at least a high school/GED education (M±SD =12±1.7 years). GEE analyses showed that buprenorphine was efficacious in maintaining abstinence across time compared to placebo. At End of Treatment, 92% of placebo and 33% of active medication participants were positive for opiates on urine drug screen (Chi-Square = 10.9, df=1; p<0.001). However, by the three month follow-up point, no differences were found between the two groups, with 83% of participants at follow-up positive for opiates.
Conclusions
Women in the CJ system who received buprenorphine prior to release from a treatment facility had fewer opiate positive UDS through the 12-weeks of treatment compared to women receiving placebo. Initiating buprenorphine in a controlled environment prior to release appears to be a viable strategy to reduce opiate use when transitioning back to the community.
doi:10.1016/j.drugalcdep.2011.06.021
PMCID: PMC3214606  PMID: 21782352
buprenorphine; Opioid Dependence; Criminal Justice; Gender; Outcome Study
16.  Methadone and buprenorphine-naloxone are effective in reducing illicit buprenorphine and other opioid use, and reducing HIV risk behavior – Outcomes of a Randomized Trial 
Drug and alcohol dependence  2013;133(2):10.1016/j.drugalcdep.2013.06.024.
Aims
Determine the extent to which buprenorphine injectors continue treatment with buprenorphine-naloxone or methadone, and the impact of these treatments on substance use and HIV risk in the Republic of Georgia.
Methods
Randomized controlled 12-week trial of daily-observed methadone or buprenorphine-naloxone followed by a dose taper, referral to ongoing treatment, and follow-up at week 20 at the Uranti Clinic in Tbilisi, Republic of Georgia. Eighty consenting treatment-seeking individuals (40/group) aged 25 and above who met ICD-10 criteria for opioid dependence with physiologic features and reported injecting buprenorphine 10 or more times in the past 30 days. Opioid use according to urine tests and self-reports, treatment retention, and HIV risk behavior as determined by the Risk Assessment Battery.
Results
Mean age of participants was 33.7 (SD5.7), 4 were female, mean history of opioid injection use was 5.8 years (SD4.6), none were HIV+ at intake or at the 12-week assessment and 73.4% were HCV+. Sixty-eight participants (85%) completed the 12-week medication phase (33 from methadone and 35 from buprenorphine/naloxone group); 37 (46%) were in treatment at the 20-week follow-up (21 from methadone and 16 from the buprenorphine/naloxone group). In both study arms, treatment resulted in a marked reduction in unprescribed buprenorphine, other opioid use, and HIV injecting risk behavior with no clinically significant differences between the two treatment arms.
Conclusions
Daily observed methadone or buprenorphine-naloxone are effective treatments for non-medical buprenorphine and other opioid use in the Republic of Georgia and likely to be useful for preventing HIV infection.
doi:10.1016/j.drugalcdep.2013.06.024
PMCID: PMC3818507  PMID: 23916321
buprenorphine abuse; treatment; Republic of Georgia
17.  Non-medical use of opioids among HIV-infected opioid dependent individuals on opioid maintenance treatment: the need for a more comprehensive approach 
Background
Opioid maintenance treatment (OMT) has a positive impact on substance use and health outcomes among HIV-infected opioid dependent patients. The present study investigates non-medical use of opioids by HIV-infected opioid-dependent individuals treated with buprenorphine or methadone.
Methods
The MANIF 2000 study is a longitudinal study that enrolled a cohort of 476 HIV-infected opioid-dependent individuals. Data were collected in outpatient hospital services delivering HIV care in France. The sample comprised all patients receiving OMT (either methadone or buprenorphine) who attended at least one follow-up visit with data on adherence to OMT (N = 235 patients, 1056 visits). Non-medical use of opioids during OMT was defined as having reported use of opioids in a non-medical context, and/or the misuse of the prescribed oral OMT by an inappropriate route of administration (injection or sniffing). After adjusting for the non-random assignment of OMT type, a model based on GEE was then used to identify predictors of non-medical use of opioids.
Results
Among the 235 patients, 144 (61.3%) and 91 (38.9%) patients were receiving buprenorphine and methadone, respectively, at baseline. Non-medical use of opioids was found in 41.6% of visits for 83% of individual patients. In the multivariate analysis, predictors of non-medical use of opioids were: cocaine, daily cannabis, and benzodiazepine use, experience of opioid withdrawal symptoms, and less time since OMT initiation.
Conclusions
Non-medical use of opioids was found to be comparable in OMT patients receiving methadone or buprenorphine. The presence of opioid withdrawal symptoms was a determinant of non-medical use of opioids and may serve as a clinical indicator of inadequate dosage, medication, or type of follow-up. Sustainability and continuity of care with adequate monitoring of withdrawal symptoms and polydrug use may contribute to reduced harms from ongoing non-medical use of opioids.
doi:10.1186/1477-7517-8-31
PMCID: PMC3286372  PMID: 22123176
opioid maintenance treatment; buprenorphine; methadone; non-medical use; HIV; withdrawal; antiretrovirals
18.  Syncope and QT prolongation among patients treated with methadone for heroin dependence in the city of Copenhagen 
Heart  2007;93(9):1051-1055.
Background
Methadone is prescribed to heroin addicts to decrease illicit opioid use. Prolongation of the QT interval in the ECG of patients with torsade de pointes (TdP) has been reported in methadone users. As heroin addicts sometimes faint while using illicit drugs, doctors might attribute too many episodes of syncope to illicit drug use and thereby underestimate the incidence of TdP in this special population, and the high mortality in this population may, in part, be caused by the proarrhythmic effect of methadone.
Methods
In this cross‐sectional study interview, ECGs and blood samples were collected in a population of adult heroin addicts treated with methadone or buprenorphine on a daily basis. Of the patients at the Drug Addiction Service in the municipal of Copenhagen, 450 (∼52%) were included. The QT interval was estimated from 12 lead ECGs. All participants were interviewed about any experience of syncope. The association between opioid dose and QT, and methadone dose and reporting of syncope was assessed using multivariate linear regression and logistic regression, respectively.
Results
Methadone dose was associated with longer QT interval of 0.140 ms/mg (p = 0.002). No association between buprenorphine and QTc was found. Among the subjects treated with methadone, 28% men and 32% women had prolonged QTc interval. None of the subjects treated with buprenorphine had QTc interval >0.440s½. A 50 mg higher methadone dose was associated with a 1.2 (95% CI 1.1 to 1.4) times higher odds for syncope.
Conclusions
Methadone is associated with QT prolongation and higher reporting of syncope in a population of heroin addicts.
doi:10.1136/hrt.2006.100180
PMCID: PMC1955005  PMID: 17344330
19.  Buprenorphine Treatment in an Urban Community Health Center: What to Expect 
Family medicine  2008;40(7):500-506.
Background
Despite new opportunities to expand buprenorphine treatment for opioid dependence, use of this treatment modality has been limited. Physicians may question their ability to successfully treat opioid-dependent patients with buprenorphine in a primary care setting. We describe a buprenorphine treatment program and treatment outcomes in an urban community health center.
Methods
We conducted retrospective chart reviews on the first 41 opioid-dependent patients treated with buprenorphine/naloxone. The primary outcome was 90-day retention in treatment.
Results
Patients’ mean age was 46 years, 70.7% were male, 58.8% Hispanic, 31.7% black, 57.5% unemployed, and 70.0% used heroin prior to treatment. Twenty-nine (70.7%) patients were retained in treatment at day 90. Compared to those not retained, patients retained in treatment were more likely to have used street methadone (0% versus 37.9%) and less likely to have used opioid analgesics (54.6% versus 20.7%) and alcohol (50.0% versus 13.8%) prior to treatment. Of the 25 patients with urine toxicology tests, 24% tested positive for opioids.
Conclusions
Buprenorphine treatment for opioid dependence in an urban community health center resulted in a 90-day retention rate of 70.7%. Type of substance use prior to treatment appeared to be associated with retention. These findings can help guide program development.
PMCID: PMC2840630  PMID: 18928077
20.  Patterns of non-compliant buprenorphine, levomethadone, and methadone use among opioid dependent persons in treatment 
Background
The non-compliant use of opioid substitution treatment (OST) medicines is widespread and well-documented. However, less is known about characteristics of non-compliant OST medicine use and the factors that predict it. The two main goals of this study are to compare characteristics of non-compliant levomethadone, methadone, and buprenorphine use and to explore factors that may differentially predict it among opioid dependent persons in treatment.
Methods
Data from 595 opioid dependent patients with non-compliant OST medicine use were analyzed. Characteristics of use between substances were compared using chi-squared tests and predictive factors were explored through multinomial logistic regressions.
Results
Non-compliant levomethadone and methadone use was characterized by more frequent parallel consumption of other psychoactive substances and intravenous use, whereas buprenorphine was more often procured without a prescription. Regarding predictive factors, methadone was perceived to relieve withdrawal symptoms better than buprenorphine and levomethadone was perceived as being better at modulating the effects of other substances and worst at enhancing mood.
Conclusions
Patterns of non-compliant use differ according to OST medicine. These patterns are considered with the reduction of non-compliant use and the improvement of treatment in mind.
doi:10.1186/1747-597X-9-19
PMCID: PMC4035758  PMID: 24885218
Buprenorphine; Levomethadone; Methadone; Opioid substitution treatment; Non-compliant use; Prescription drugs; Opioid maintenance therapy; Heroin dependence; Opioid dependence
21.  Illicit Use of Buprenorphine/Naloxone Among Injecting and Noninjecting Opioid Users 
Journal of addiction medicine  2011;5(3):175-180.
Objectives
We examined the use, procurement, and motivations for the use of diverted buprenorphine/naloxone among injecting and noninjecting opioid users in an urban area.
Methods
A survey was self-administered among 51 injecting opioid users and 49 noninjecting opioid users in Providence, RI. Participants were recruited from a fixed-site syringe exchange program and a community outreach site between August and November 2009.
Results
A majority (76%) of participants reported having obtained buprenorphine/naloxone illicitly, with 41% having done so in the previous month. More injection drug users (IDUs) than non-IDUs reported the use of diverted buprenorphine/naloxone (86% vs 65%, P = 0.01). The majority of participants who had used buprenorphine/naloxone reported doing so to treat opioid withdrawal symptoms (74%) or to stop using other opioids (66%) or because they could not afford drug treatment (64%). More IDUs than non-IDUs reported using diverted buprenorphine/naloxone for these reasons. Significantly more non-IDUs than IDUs reported ever using buprenorphine/naloxone to “get high” (69% vs 32%, P < 0.01). The majority of respondents, both IDUs and non-IDUs, were interested in receiving treatment for opioid dependence, with greater reported interest in buprenorphine/naloxone than in methadone. Common reasons given for not being currently enrolled in a buprenorphine/naloxone program included cost and unavailability of prescribing physicians.
Conclusions
The use of diverted buprenorphine/naloxone was common in our sample. However, many opioid users, particularly IDUs, were using diverted buprenorphine/naloxone for reasons consistent with its therapeutic purpose, such as alleviating opioid withdrawal symptoms and reducing the use of other opioids. These findings highlight the need to explore the full impact of buprenorphine/naloxone diversion and improve the accessibility of buprenorphine/naloxone through licensed treatment providers.
doi:10.1097/ADM.0b013e3182034e31
PMCID: PMC3157053  PMID: 21844833
buprenorphine; buprenorphine/naloxone; diversion; injection drug use; opiate dependence
22.  The pharmacodynamic and pharmacokinetic profile of intranasal crushed buprenorphine and buprenorphine/naloxone tablets in opioid abusers 
Addiction (Abingdon, England)  2011;106(8):1460-1473.
Aims
Sublingual buprenorphine and buprenorphine/naloxone are efficacious opioid dependence pharmacotherapies, but there are reports of their diversion and misuse by the intranasal route. The study objectives were to characterize and compare their intranasal pharmacodynamic and pharmacokinetic profiles.
Design
A randomized, double-blind, placebo-controlled, crossover study.
Setting
An in-patient research unit at the University of Kentucky.
Participants
Healthy adults (n=10) abusing, but not physically dependent on, intranasal opioids.
Measurements
Six sessions (72 hours apart) tested five intranasal doses [0/0, crushed buprenorphine (2, 8 mg), crushed buprenorphine/naloxone (2/0.5, 8/2 mg)] and one intravenous dose (0.8 mg buprenorphine/0.2 mg naloxone for bioavailability assessment). Plasma samples, physiological, subject- and observer-rated measures were collected before and for up to 72 hours after drug administration.
Findings
Both formulations produced time- and dose-dependent increases on subjective and physiological mu-opioid agonist effects (e.g. ‘liking’, miosis). Subjects reported higher subjective ratings and street values for 8 mg compared to 8/2 mg, but these differences were not statistically significant. No significant formulation differences in peak plasma buprenorphine concentration or time-course were observed. Buprenorphine bioavailability was 38–44% and Tmax was 35–40 minutes after all intranasal doses. Naloxone bioavailability was 24% and 30% following 2/0.5 and 8/2 mg, respectively.
Conclusions
It is difficult to determine if observed differences in abuse potential between intranasal buprenorphine and buprenorphine/naloxone are clinically relevant at the doses tested. Greater bioavailability and faster onset of pharmacodynamic effects compared to sublingual administration suggests a motivation for intranasal misuse in non-dependent opioid abusers. However, significant naloxone absorption from intranasal buprenorphine/naloxone administration may deter the likelihood of intranasal misuse of buprenorphine/naloxone, but not buprenorphine, in opioid-dependent individuals.
doi:10.1111/j.1360-0443.2011.03424.x
PMCID: PMC3776483  PMID: 21395892
23.  Induction of Pregnant Women onto Opioid-agonist Maintenance Medication: An Analysis of Withdrawal Symptoms and Study Retention 
Drug and alcohol dependence  2013;132(0):329-334.
Background
Induction onto buprenorphine during pregnancy may be more challenging than induction onto methadone. This study explores factors predicting withdrawal intensities and compares trajectories of withdrawal during the induction phase between opioid-dependent women randomly assigned to methadone or buprenorphine.
Methods
A secondary analysis was conducted on data from 175 opioid-dependent pregnant women inducted onto buprenorphine or methadone subsequent to stabilization on morphine sulfate. ANOVA analyses were conducted to determine differences between mean peak CINA scores by medication and completion status. General linear mixed models were fitted to compare trajectories of CINA scores between methadone and buprenorphine conditions, and between study dropouts and completers within the buprenorphine condition.
Results
Both buprenorphine and methadone patients experienced withdrawal categorized as minimal by the CINA scoring system. Significant differences in mean peak CINA scores for the first 72 hours of induction were found between the methadone (4.5; SD=0.4) and buprenorphine conditions (6.9; SD=0.4), with buprenorphine patients exhibiting higher mean peak CINA scores [F (3, 165) =9.70, p<0.001]. The trajectory of CINA scores showed buprenorphine patients exhibiting a sharper increase in mean CINA scores than methadone patients [F (1, 233) =8.70, p=0.004]. There were no differences in mean peak CINA scores [F (3, 77) =0.08, p=0.52] or in trajectory of CINA scores [F (1, 166) =0.42, p=0.52] between buprenorphine study dropouts and completers.
Conclusion
While mean peak CINA score was significantly higher in the buprenorphine condition than the methadone condition, neither medication condition experienced substantial withdrawal symptoms. Further research on factors related to successful induction to buprenorphine treatment in pregnant women is needed.
doi:10.1016/j.drugalcdep.2013.02.031
PMCID: PMC3732530  PMID: 23523131
pregnancy; opioid dependence; buprenorphine induction; CINA; opioid withdrawal; methodone induction
24.  Interaction Between Buprenorphine and Atazanavir or Atazanavir/Ritonavir 
Drug and Alcohol Dependence  2007;91(2-3):269-278.
Opioid addiction and HIV disease frequently co-occur. Adverse drug interactions have been reported between methadone and some HIV medications, but less is known about interactions between buprenorphine, an opioid partial agonist used to treat opioid dependence, and HIV therapeutics. This study examined drug interactions between buprenorphine and the protease inhibitors atazanavir and atazanavir/ritonavir. Opioid-dependent, buprenorphine/naloxone-maintained, HIV-negative volunteers (n=10 per protease inhibitor) participated in two 24-hour sessions to determine pharmacokinetics of (1) buprenorphine and (2) buprenorphine and atazanavir (400 mg daily) or atazanavir/ritonavir (300/100 mg daily) following administration for 5 days. Objective opiate withdrawal scale scores and Mini-Mental State Examination were determined prior to and following antiretroviral administration to examine pharmacodynamic effects. Pharmacokinetics of atazanavir and atazanavir/ritonavir were compared in subjects and matched, healthy controls (n=10 per protease inhibitor) to determine effects of buprenorphine. With atazanavir and atazanavir/ritonavir, respectively concentrations of buprenorphine (p<0.001, p<0.001), norbuprenorphine (p=0.026, p=0.006), buprenorphine glucuronide (p=0.002, p<0.001), and norbuprenorphine glucuronide (NS, p=0.037) increased. Buprenorphine treatment did not significantly alter atazanavir or ritonavir concentrations. Three buprenorphine/naloxone-maintained participants reported increased sedation with atazanavir/ritonavir. Atazanavir or atazanavir/ritonavir may increase buprenorphine and buprenorphine metabolite concentrations and might require a decreased buprenorphine dose.
doi:10.1016/j.drugalcdep.2007.06.007
PMCID: PMC3272856  PMID: 17643869
buprenorphine/naloxone; atazanavir; ritonavir; drug interactions
25.  Tobacco Addiction and Smoking Status in Heroin Addicts under Methadone vs. Buprenorphine Therapy 
Aims of the present investigation were: (i) to assess the prevalence of current smokers and relative smoking status among a large number of heroin addicts attending opioid-substitution therapy prevalence; (ii) to evaluate the relationship between the type (methadone, buprenorphine) and dosage of opioid substitution therapy and nicotine dependence. Three hundred and five (305) heroin addicts under opioid-substitution therapy were recruited at five Addiction Units. All participants completed a questionnaire assessing sociodemographic information, type and dose of opioid-substitution therapy, smoking history and status, Fagerström Test for Nicotine Dependence (FTND), and the Zung Self-Rating Depression scale (SDS). 298 subjects, out of 305 (97.2%) were smokers, with an average of 20.5 cigarette/day and a median FTND of 6. Our data confirmed the high prevalence of smokers among heroin addicts, the highest described in the literature to date among heroin addicts under substitution therapies, without any significant difference between methadone vs. buprenorphine therapy groups. There was no correlation between dose of methadone or buprenorphine and average number of cigarettes/day. Patients in substance abuse treatment very frequently smoke cigarettes and often die of tobacco-related diseases. Substance abuse treatment programs too often ignore tobacco use. We hope that these findings will help to incorporate smoking cessation in substance abuse treatments.
doi:10.3390/ijerph9030932
PMCID: PMC3367288  PMID: 22690174
tobacco smoking; methadone; buprenorphine; heroin; opioid substitution therapy

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