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1.  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
2.  Interactions Between Buprenorphine and the Protease Inhibitors Darunavir-Ritonavir and Fosamprenavir-Ritonavir 
In adults receiving buprenorphine-naloxone maintenance, buprenorphine pharmacokinetics were not changed significantly by 15-day coadministration of darunavir-ritonavir or fosamprenavir-ritonavir. The pharmacokinetics of the protease inhibitors did not differ from those in matched controls receiving only the protease inhibitors.
Background. This study examined drug interactions between buprenorphine, a partial opioid agonist used for opioid dependence treatment and pain management, and the protease inhibitors (PIs) darunavir-ritonavir and fosamprenavir-ritonavir.
Methods. The pharmacokinetics of buprenorphine and its metabolites and symptoms of opioid withdrawal or excess were compared in opioid-dependent, buprenorphine-naloxone–maintained, human immunodeficiency virus (HIV)–negative volunteers (11 for darunavir-ritonavir and 10 for fosamprenavir-ritonavir) before and after 15 days of PI administration. PI pharmacokinetics and adverse effects were compared between the buprenorphine-maintained participants and an equal number of sex-, age-, race-, and weight-matched, healthy, non–opioid-dependent volunteers who received darunavir-ritonavir or fosamprenavir-ritonavir but not buprenorphine.
Results. There were no significant changes in buprenorphine or PI plasma levels and no significant changes in medication adverse effects or opioid withdrawal. Increased concentrations of the inactive metabolite buprenorphine-3-glucuronide suggested that darunavir-ritonavir and fosamprenavir-ritonavir induced glucuronidation of buprenorphine.
Conclusions. Dose adjustments are not likely to be necessary when buprenorphine and darunavir-ritonavir or fosamprenavir-ritonavir are coadministered for the treatment of opioid dependence and HIV disease.
doi:10.1093/cid/cir799
PMCID: PMC3258270  PMID: 22100576
3.  A Comparison of Buprenorphine + Naloxone to Buprenorphine and Methadone in the Treatment of Opioid Dependence during Pregnancy: Maternal and Neonatal Outcomes 
Given that buprenorphine + naloxone is prescribed for opioid-dependent pregnant women, it is important to examine the extent to which it differs from buprenorphine alone, methadone, or methadone-assisted withdrawal on neonatal and maternal outcomes. Summary statistics on maternal and neonatal outcomes were collected from 7 previously published studies examining treatment for opioid-dependent pregnant women that represented a range of research methodologies. Outcomes from these studies were compared to the same outcomes for 10 women treated with the combined buprenorphine + naloxone product. There were no significant differences in maternal outcomes for buprenorphine + naloxone compared to buprenorphine, methadone, or methadone-assisted withdrawal. Preliminary findings suggest no significant adverse maternal or neonatal outcomes related to the use of buprenorphine + naloxone for the treatment of opioid dependence during pregnancy. However, further research should examine possible differences between buprenorphine + naloxone and buprenorphine alone or methadone in fetal physical development.
doi:10.4137/SART.S10955
PMCID: PMC3603528  PMID: 23531704
buprenorphine; methadone; opioid dependence; pregnancy; neonates
4.  Buprenorphine/naloxone Treatment in Primary Care is Associated with Decreased HIV Risk Behaviors 
Methadone treatment reduces HIV risk but the effects of primary care-based buprenorphine/naloxone on HIV risk are unknown. The purpose of the current study was to determine whether primary care-based buprenorphine/naloxone was associated with decreased HIV risk behavior. We conducted a longitudinal analysis of 166 opioid dependent persons (129 men and 37 women) receiving buprenorphine/naloxone treatment in a primary care clinic. We compared baseline, 12 and 24-week overall, drug-related and sex-related HIV risk behaviors using the AIDS/HIV Risk Inventory (ARI). Buprenorphine/naloxone treatment was associated with significant reductions in overall and drug-related ARI scores from baseline to 12 and 24-weeks. Intravenous drug use in the past 3 months was endorsed by 37%, 12%, and 7%, of patients at baseline, 12 weeks and 24 weeks, respectively; p < 0.001. Sex while you or your partner were “high” was endorsed by 64%, 13%, and 15% of patients at baseline, 12 weeks and 24 weeks, respectively; p<0.001. Inconsistent condom use during sex with a steady partner was high at baseline and did not change over time. We conclude that primary care-based buprenorphine/naloxone treatment is associated with decreased drug-related HIV risk but additional efforts may be needed to address sex-related HIV risk when present. (ClinicalTrials.gov number, NCT00023283).
doi:10.1016/j.jsat.2007.08.004
PMCID: PMC2587397  PMID: 17933486
Buprenorphine; HIV/AIDS; Risk Reduction Behavior; Treatment; Prevention
5.  Lack of Clinically Significant Drug Interactions between Nevirapine and Buprenorphine 
This study was conducted to determine whether drug interactions of clinical importance occur between buprenorphine, an opioid partial agonist medication used in treatment of opioid dependence, and the nonnucleoside reverse transcriptase inhibitor (NNRTI) nevirapine. Opioid-dependent, buprenorphine/naloxone-maintained, HIV-negative volunteers (n=7) participated in 24-hour sessions to determine the pharmacokinetics of buprenorphine alone and of buprenorphine and nevirapine following administration of 200 mg nevirapine daily for 15 days. Opiate withdrawal symptoms, cognitive effects, and adverse events were determined prior to and following nevirapine administration. Modest decreases were observed for AUC for buprenorphine and its metabolites. There was a trend for more rapid clearance of both buprenorphine (p = .08) and buprenorphine-3-glucuronide (p = .08). While no single effect reached statistical significance, the joint probability that the consistent declines in all measures of exposure were due to chance was extremely low, indicating that nevirapine significantly reduces overall exposure to buprenorphine and buprenorphine metabolites. Clinically significant consequences of the interaction were not observed. Buprenorphine did not alter nevirapine pharmacokinetics. Dose adjustments of either buprenorphine or nevirapine are not likely to be necessary when these drugs are coadministered for the treatment of opiate dependence and HIV disease.
doi:10.1111/j.1521-0391.2009.00006.x
PMCID: PMC3723410  PMID: 20132119
6.  Pharmacotherapy in the Treatment of Addiction: Methadone 
Journal of addictive diseases  2010;29(2):200-216.
Methadone maintenance treatment is the most widely available pharmacotherapy for opioid addiction and has been shown over a period of 40 years to be an effective and safe treatment. While women comprise approximately 40% of clients currently being treated in MMT programs, comparatively little research geared specifically toward this group has been published. This article begins with an overview of neurobiological studies on opioid addiction, including a discussion of gender differences, followed by a review of the pharmacology of methadone The authors then examine the particular needs and differences of women being treated in MMTs, including co-dependence with other substances, women’s health issues and psychosocial needs unique to this population. In conclusion, research shows that women have different substance abuse treatment needs in comparison to their male counterparts. One New York City MMT program that has attempted to address these differences is highlighted.
doi:10.1080/10550881003684798
PMCID: PMC2885886  PMID: 20407977
women; methadone maintenance; pharmacotherapy; gender differences; addiction; opiate addiction
7.  Buprenorphine and Buprenorphine/Naloxone Diversion, Misuse, and Illicit Use: An International Review 
Current drug abuse reviews  2011;4(1):28-41.
The diversion, misuse, and non-medically supervised use of buprenorphine and buprenorphine/naloxone by opioid users are reviewed. Buprenorphine and buprenorphine/naloxone are used globally as opioid analgesics and in the treatment of opioid dependency. Diversion of buprenorphine and buprenorphine/naloxone represents a complex medical and social issue, and has been widely documented in various geographical regions throughout the world.
We first discuss the clinical properties of buprenorphine and its abuse potential. Second, we discuss its diversion and illicit use on an international level, as well as motivations for those activities. Third, we examine the medical risks and benefits of buprenorphine’s non-medically supervised use and misuse. These risks and benefits include the effect of buprenorphine’s use on HIV risk and the risk of its concomitant use with other medications and drugs of abuse. Finally, we discuss the implications of diversion, misuse, and non-medically supervised use (including potential measures to address issues of diversion); and potential areas for further research.
PMCID: PMC3154701  PMID: 21466501
Buprenorphine; buprenorphine/naloxone; diversion; injection drug use; self treatment; Suboxone; Subutex; opioid dependence; opioid abuse; opiate abuse; opiate dependence
8.  Top Manager Effects on Buprenorphine Adoption in Outpatient Substance Abuse Treatment Programs 
To examine the influence of top managers’ characteristics on the adoption of buprenorphine for opioid dependence among U.S. outpatient substance abuse treatment units, this investigation analyzed a cross-sectional national study of 547 such units in the 2004–2005 wave of the Drug Abuse Treatment System Survey. Administrators reported their demographics, training, and treatment orientation, as well as features of the unit and its pattern of use of buprenorphine. Nationally, 15.8% of programs offered any buprenorphine services. Greater adoption of buprenorphine correlated with directors’ younger age, longer tenure, male gender, and weaker endorsement of abstinence as the most important treatment goal. Availability of naltrexone and medical services also correlated positively with buprenorphine adoption. The authors conclude that leaders’ characteristics are related to the adoption of innovative practices in addiction treatment programs. Future work should examine whether leadership development for community addiction programs might speed up the diffusion of buprenorphine and other innovative, evidence-based practices.
doi:10.1007/s11414-009-9169-z
PMCID: PMC3682405  PMID: 19296223
9.  Bringing Buprenorphine-Naloxone Detoxification to Community Treatment Providers: The NIDA Clinical Trials Network Field Experience 
In October 2002, the U.S. Food and Drug Administration approved buprenorphine-naloxone (Suboxone®) sublingual tablets as an opioid dependence treatment available for use outside traditionally licensed opioid treatment programs. The NIDA Center for Clinical Trials Network (CTN) sponsored two clinical trials assessing buprenorphine-naloxone for short-term opioid detoxification. These trials provided an unprecedented field test of its use in twelve diverse community-based treatment programs. Opioid-dependent men and women were randomized to a thirteen-day buprenorphine-naloxone taper regimen for short-term opioid detoxification. The 234 buprenorphine-naloxone patients averaged 37 years old and used mostly intravenous heroin. Direct and rapid induction onto buprenorphine-naloxone was safe and well tolerated. Most patients (83%) received 8 mg buprenorphine-2 mg naloxone on the first day and 90% successfully completed induction and reached a target dose of 16mg buprenorphine-4 mg naloxone in three days. Medication compliance and treatment engagement was high. An average of 81% of available doses was ingested, and 68% of patients completed the detoxification. Most (80.3%) patients received some ancillary medications with an average of 2.3 withdrawal symptoms treated. The safety profile of buprenorphine-naloxone was excellent. Of eighteen serious adverse events reported, only one was possibly related to buprenorphine-naloxone. All providers successfully integrated buprenorphine-naloxone into their existing treatment milieus. Overall, data from the CTN field experience suggest that buprenorphine-naloxone is practical and safe for use in diverse community treatment settings, including those with minimal experience providing opioid-based pharmacotherapy and/or medical detoxification for opioid dependence.
doi:10.1080/10550490490440807
PMCID: PMC1255908  PMID: 15204675
10.  From Research to the Real World: Buprenorphine in the Decade of the Clinical Trials Network 
Journal of substance abuse treatment  2010;38(Suppl 1):S53-S60.
The National Institute on Drug Abuse (NIDA) established the National Drug Abuse Treatment Clinical Trials Network (CTN) in 1999 to bring researchers and treatment providers together to develop a clinically relevant research agenda. Initial CTN efforts addressed the use of buprenorphine, a mu-opioid partial agonist, as treatment for opioid dependence. Strong evidence of buprenorphine's therapeutic efficacy was demonstrated in clinical trials involving several thousand opioid-dependent participants, and in 2002, the FDA approved buprenorphine for the treatment of opioid dependence. With the advent of a sublingual tablet containing both buprenorphine and naloxone to mitigate abuse and diversion (Suboxone®), buprenorphine appeared poised to be the first-line treatment for opioid addiction. Notwithstanding its many attributes, certain implementation barriers remained to be addressed in CTN studies, and these efforts have brought a body of knowledge on buprenorphine to front-line clinicians. The purpose of this article is to review CTN-based buprenorphine research and related efforts to overcome challenges to the implementation of buprenorphine therapy in mainstream practice. Furthermore, this paper explores current issues and future challenges that may require additional CTN efforts.
doi:10.1016/j.jsat.2010.01.009
PMCID: PMC2853172  PMID: 20307796
11.  Buprenorphine vs methadone treatment: A review of evidence in both developed and developing worlds 
Heroin dependence is a major health and social problem associated with increased morbidity and mortality that adversely affects social circumstances, productivity, and healthcare and law enforcement costs. In the UK and many other Western countries, both methadone and buprenorphine are recommended by the relevant agencies for detoxification from heroin and for opioid maintenance therapy. However, despite obvious benefits due to its unique pharmacotherapy (eg, greatly reduced risk of overdose), buprenorphine has largely failed to overtake methadone in managing opioid addiction. The experience from the developing world (based on data from India) is similar. In this article we compare the advantages and disadvantages of the use methadone and buprenorphine for the treatment of opioid addiction from both a developed and developing world perspective; and explore some of the reasons why buprenorphine has not fulfilled the expectations predicted by many in the addictions field.
doi:10.4103/0976-3147.91934
PMCID: PMC3271614  PMID: 22346191
Addiction; buprenorphine; detoxification; maintenance; methadone; opiate
12.  Drug interactions associated with methadone, buprenorphine, cocaine, and HIV medications: implications for pregnant women 
Life Sciences  2010;88(21-22):953-958.
Pregnancy in substance-abusing women with HIV/AIDS presents a complex clinical challenge. Opioid-dependent women need treatment with opioid therapy during pregnancy to protect the health of mother and developing fetus. However, opioid therapies, methadone and buprenorphine, may have drug interactions with some HIV medications that can have adverse effects leading to suboptimal clinical outcomes. Further, many opioid-dependent individuals have problems with other forms of substance abuse, for example, cocaine abuse, that could also contribute to poor clinical outcomes in a pregnant woman. Physiological changes, including increased plasma volume and increased hepatic and renal blood flow, occur in the pregnant woman as the pregnancy progresses and may alter medication needs with the potential to exacerbate drug interactions, although there is sparse literature on this issue. Knowledge of possible drug interactions between opioids, other abused substances such as cocaine, HIV therapeutics, and other frequently required medications such as antibiotics and anticonvulsants is important to assuring the best possible outcomes in the pregnant woman with opioid dependence and HIV/AIDS.
doi:10.1016/j.lfs.2010.09.016
PMCID: PMC3272849  PMID: 20965297
pregnancy; substance abuse; HIV disease; cocaine; methadone; buprenorphine; drug interactions
13.  Rifampin, but not Rifabutin, May Produce Opiate Withdrawal in Buprenorphine-Maintained Patients* 
Drug and Alcohol Dependence  2011;118(2-3):326-334.
Background
This series of studies examines the pharmacokinetic/pharmacodynamic interactions between buprenorphine, an opioid partial agonist increasingly used in treatment of opioid dependence, and rifampin, a medication used as a first line treatment for tuberculosis; or rifabutin, an alternative antituberculosis medication.
Methods
Opioid-dependent individuals on stable doses of buprenorphine/naloxone underwent two, 24-hour blood sampling studies: 1. for buprenorphine pharmacokinetics and 2. following 15 days of rifampin 600 mg daily or rifabutin 300 mg daily for buprenorphine and rifampin or rifabutin pharmacokinetics.
Results
Rifampin administration produced significant reduction in plasma buprenorphine concentrations (70% reduction in mean area under the curve (AUC); p=<0·001) and onset of opiate withdrawal symptoms in 50% of participants (p=0·02). While rifabutin administration to buprenorphine-maintained subjects resulted in a significant decrease in buprenorphine plasma concentrations (35% decrease in AUC; p<0·001) no opiate withdrawal was seen. Compared with historical control data, buprenorphine had no significant effect on rifampin pharmacokinetics, but was associated with 22% lower rifabutin mean AUC (p=0·009), although rifabutin and its active metabolite concentrations remained in the therapeutic range.
Conclusions
Rifampin is a more potent inducer of buprenorphine metabolism than rifabutin with pharmacokinetic and pharmacodynamic adverse consequences. Those patients requiring rifampin treatment for tuberculosis and receiving buprenorphine therapy are likely to require an increase in buprenorphine dose to prevent withdrawal symptoms. Rifabutin administration was associated with decreases in buprenorphine plasma concentrations, but no clinically significant adverse events were observed.
doi:10.1016/j.drugalcdep.2011.04.013
PMCID: PMC3272858  PMID: 21596492
buprenorphine/naloxone; rifampin; rifabutin; tuberculosis; opioid addiction; drug interactions
14.  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
15.  Budgetary impact analysis of buprenorphine-naloxone combination (Suboxone®) in Spain 
Background
Opioid addiction is a worldwide problem. Agonist opioid treatment (AOT) is the most widespread and frequent pharmacotherapeutic approach. Methadone has been the most widely used AOT, but buprenorphine, a partial μ-opiod agonist and a κ-opiod antagonist, is fast gaining acceptance. The objective was to assess the budgetary impact in Spain of the introduction of buprenorphine-naloxone (B/N) combination.
Methods
A budgetary impact model was developed to estimate healthcare costs of the addition of B/N combination to the therapeutic arsenal for treating opioid dependent patients, during a 3-year period under the National Health System perspective. Inputs for the model were obtained from the specialized scientific literature. Detailed information concerning resource consumption (drug cost, logistics, dispensing, medical, psychiatry and pharmacy supervision, counselling and laboratory test) was obtained from a local expert panel. Costs are expressed in euros (€, 2010).
Results
The number of patients estimated to be prescribed B/N combination was 2,334; 2,993 and 3,589 in the first, second and third year respectively. Total budget is €85,766,129; €79,855,471 and €79,137,502 in the first, second and third year for the scenario without B/N combination. With B/N combination the total budget would be €86,589,210; €80,398,259 and €79,708,964 in the first, second and third year of the analyses. Incremental cost/patient comparing the addition of the B/N combination to the scenario only with methadone is €10.58; €6.98 and €7.34 in the first, second and third year respectively.
Conclusion
Addition of B/N combination would imply a maximum incremental yearly cost of €10.58 per patient compared to scenario only with methadone and would provide additional benefits.
doi:10.1186/2191-1991-2-3
PMCID: PMC3402931  PMID: 22828157
Buprenorphine-naloxone; Methadone; Budgetary impact; Opioid dependence; Spain
16.  Opioid Dependence Treatment: Options In Pharmacotherapy 
Expert opinion on pharmacotherapy  2009;10(11):1727-1740.
The development of effective treatments for opioid dependence is of great importance given the devastating consequences of the disease. Pharmacotherapies for opioid addiction include opioid agonists, partial agonists, opioid antagonists, and alpha-2-adrenergic agonists, which are targeted toward either detoxification or long-term agonist maintenance. Agonist maintenance therapy is currently the recommended treatment for opioid dependence due to its superior outcomes relative to detoxification. Detoxification protocols have limited long term efficacy and patient discomfort remains a significant therapy challenge. Buprenorphine’s effectiveness relative to methadone remains a controversy and may be most appropriate for patients in need of low doses of agonist treatment. Buprenorphine appears superior to alpha-2 agonists, however, and office-based treatment with buprenorphine in the US is gaining support. Studies of sustained-release formulations of naltrexone suggest improved effectiveness for retention and sustained abstinence, however, randomized clinical trials are needed.
doi:10.1517/14656560903037168
PMCID: PMC2874458  PMID: 19538000
opioid; opiate; pharmacotherapy; heroin
17.  Are male neonates more vulnerable to neonatal abstinence syndrome than female neonates? 
Gender medicine  2011;8(6):355-364.
Objective
Prior studies have shown an increased vulnerability among males, to adverse outcomes during the postnatal period. The majority of children exposed to opioids and other medication in utero develop a neonatal abstinence syndrome (NAS), yet individual predisposition for NAS is poorly understood. This investigation examines the role of neonatal sex in the postnatal period, for neonates exposed to standardized opioid maintenance treatment in utero with a focus on the neonatal abstinence syndrome (NAS) regarding severity, medication requirements and duration.
Patients and Methods
This is a secondary analysis of data collected in a prospective randomized, double-blind, double-dummy multi-center trial examining the comparative safety and efficacy of methadone and buprenorphine during pregnancy (Maternal Opioid Treatment: Human Experimental research MOTHER – study). 131 neonates born to opioid-dependent women randomized at six US sites (n=74) and one European site (n=37) were analyzed. Sex-based differences in birth weight, length, head circumference, NAS duration, NAS severity, and treatment parameters of full-term neonates were assessed.
Results
Males had a significantly higher birth weight (p=0.027) and head circumference (p=0.017) than females, with no significant sex difference in rates of preterm delivery. No significant sex-related differences were found for NAS development, severity, duration, or medication administered with non significant differences in concomitant drug consumption during pregnancy (p =0.959).
Conclusions
This unique prospective study shows similar postnatal vulnerability for both sexes, suggesting that factors other than sex are the major determinants of clinically significant NAS.
doi:10.1016/j.genm.2011.10.001
PMCID: PMC3241965  PMID: 22088886
opioid dependence; methadone; buprenorphine; pregnancy; neonatal abstinence syndrome; sex differences
18.  Comparative Profiles of Men and Women with Opioid Dependence: Results from a National Multisite Effectiveness Trial 
Background
Accumulating evidence indicates important gender differences in substance use disorders. Little is known, however, about gender differences and opioid use disorders.
Objectives
To compare demographic characteristics, substance use severity, and other associated areas of functioning (as measured by the Addiction Severity Index–Lite; ASI) among opioid-dependent men and women participating in a multisite effectiveness trial.
Methods
Participants were 892 adults screened for the National Institute on Drug Abuse’s (NIDA) Clinical Trials Network (CTN) investigation of the effectiveness of two buprenorphine tapering schedules.
Results
The majority of men and women tested positive for oxycodone (68% and 65%, respectively) and morphine (89% each). More women than men tested positive for amphetamines (4% vs. 1%, p<0.01), methamphetamine (11% vs. 4%, p<0.01) and phencyclidine (8% vs. 4%, p=0.02). More men than women tested positive for methadone (11% vs. 6%, p=0.05) and marijuana (22% vs. 15%, p=0.03). Craving for opioids was significantly higher among women (p<0.01). Men evidenced higher alcohol (p<0.01) and legal (p=0.04) ASI composite scores, whereas women had higher drug (p<0.01), employment (p<0.01), family (p<0.01), medical (p<0.01), and psychiatric (p<0.01) ASI composite scores. Women endorsed significantly more current and past medical problems.
Conclusions
Important gender differences in the clinical profiles of opioid-dependent individuals were observed with regard to substance use severity, craving, medical conditions, and impairment in associated areas of functioning. The findings enhance understanding of the characteristics of treatment-seeking men and women with opioid dependence, and may be useful in improving identification, prevention, and treatment efforts for this challenging and growing population.
doi:10.3109/00952990.2011.596982
PMCID: PMC3164783  PMID: 21854273
19.  Office-Based Buprenorphine for Patients with Opioid Dependence 
Annals of internal medicine  2008;148(9):662-670.
The profile of opioid dependence in the United States is changing. Abuse of prescription opioids is more common than that of illicit opioids. Recent data indicate that there are approximately 1.6 million individuals with prescription opioid abuse or dependence and 323,000 with heroin abuse or dependence. Despite this prevalence, nearly 80% of these individuals go untreated. One option for expanding treatment is the use of buprenorphine and the buprenorphine/naloxone combination. Buprenorphine is a partial opioid agonist that can be prescribed by trained Internists and dispensed at pharmacies.
The case-based discussion in this paper addresses the clinical presentation of a patient with opioid dependence and describes the relatively new practice of office-based treatment with buprenorphine/naloxone. It examines the different components of treatment, the role of the Internist in providing this treatment, and the logistics of treating this growing and multi-faceted patient population.
PMCID: PMC3694223  PMID: 18458279
20.  Abuse liability of intravenous buprenorphine/naloxone and buprenorphine alone in buprenorphine-maintained intravenous heroin abusers 
Addiction (Abingdon, England)  2010;105(4):709-718.
BACKGROUND
Sublingual buprenorphine is an effective maintenance treatment for opioid dependence, yet intravenous buprenorphine misuse occurs. A buprenorphine/naloxone formulation was developed to mitigate this misuse risk. This randomized, double-blind, crossover study was conducted to assess the intravenous abuse potential of buprenorphine/naloxone compared with buprenorphine in buprenorphine-maintained injection drug users (IDUs).
METHODS
Intravenous heroin users (n=12) lived in the hospital for 8–9 weeks and were maintained on each of 3 different sublingual buprenorphine doses (2 mg, 8 mg, 24 mg). Under each maintenance dose, participants completed laboratory sessions during which the reinforcing and subjective effects of intravenous placebo, naloxone, heroin, and low and high doses of buprenorphine and buprenorphine/naloxone were examined. Every participant received each test dose under the 3 buprenorphine maintenance dose conditions.
RESULTS
Intravenous buprenorphine/naloxone was self-administered less frequently than buprenorphine or heroin (P < 0.0005). Participants were most likely to self-administer drug intravenously when maintained on the lowest sublingual buprenorphine dose. Subjective ratings of “drug liking” and “desire to take the drug again” were lower for buprenorphine/naloxone than for buprenorphine or heroin (P = 0.0001). Participants reported that they would pay significantly less money for buprenorphine/naloxone than for buprenorphine or heroin (P < 0.05). Seven adverse events were reported; most were mild and transient.
CONCLUSIONS
These data suggest that although the buprenorphine/naloxone combination has intravenous abuse potential, it is lower than for buprenorphine alone, particularly when participants received higher maintenance dosages and lower buprenorphine/naloxone challenge doses. Buprenorphine/naloxone may be a reasonable option for managing the risk for buprenorphine misuse during opioid dependence treatment.
doi:10.1111/j.1360-0443.2009.02843.x
PMCID: PMC3489277  PMID: 20403021
buprenorphine/naloxone; abuse liability; opioid dependence
21.  Factors affecting willingness to provide buprenorphine treatment 
Buprenorphine is an effective long-term opioid agonist treatment. As the only pharmacological treatment for opioid dependence readily available in office-based settings, buprenorphine may facilitate a historic shift in addiction treatment from treatment facilities to general medical practices. Although many patients have benefited from the availability of buprenorphine in the United States, almost half of current prescribers are addiction specialists suggesting that buprenorphine treatment has not yet fully penetrated general practice settings. We examined factors affecting willingness to offer buprenorphine treatment among physicians with different levels of prescribing experience. Based on their prescribing practices, physicians were classified as experienced, novice, or as a nonprescriber and asked to assess the extent to which a list of factors impacted their prescription of buprenorphine. Several factors affected willingness to prescribe buprenorphine for all physicians: staff training; access to counseling and alternate treatment; visit time; buprenorphine availability; and pain medications concerns. Compared with other physicians, experienced prescribers were less concerned about induction logistics and access to expert consultation, clinical guidelines, and mental health services. They were more concerned with reimbursement. These data provide important insight into physician concerns about buprenorphine and have implications for practice, education, and policy change that may effectively support widespread adoption of buprenorphine.
doi:10.1016/j.jsat.2008.06.006
PMCID: PMC2866292  PMID: 18715741
Buprenorphine; Opioid-related disorders; HIV; Physician’s practice patterns; Willingness
22.  Co-occurring amphetamine use and associated medical and psychiatric comorbidity among opioid-dependent adults: results from the Clinical Trials Network 
Background
In response to the rising rate of treatment admissions related to illicit use of amphetamines (eg, methamphetamine), we examined the prevalence of amphetamine use among treatment-seeking, opioid-dependent adults, explored whether amphetamine users were as likely as nonamphetamine users to enroll in opioid-dependence treatment trials, and determined whether amphetamine users manifested greater levels of medical and psychiatric comorbidity than nonusers.
Methods
The sample included 1257 opioid-dependent adults screened for participation in three-multisite studies of the National Drug Abuse Treatment Clinical Trials Network (CTN001-003), which studied the effectiveness of buprenorphine for opioid detoxification under varying treatment conditions. Patients were recruited from 23 addiction treatment programs across the US. Medical and psychiatric comorbidity were examined by past-month amphetamine use (current vs former) and route of administration. Five mutually exclusive groups were examined, ie, nonusers, current amphetamine injectors, current amphetamine noninjectors, former amphetamine injectors, and former amphetamine noninjectors.
Results
Of the sample (n = 1257), 22.3% had a history of regular amphetamine use. Of the 280 amphetamine users, 30.3% reported injection as their primary route. Amphetamine users were more likely than nonusers to be white and use more substances. Amphetamine users were as likely as non-users to enroll in treatment trials. Bivariate analyses indicated elevated rates of psychiatric problems (depression, anxiety, hallucinations, cognitive impairment, violence, suicidal thoughts/attempts) and medical illnesses (dermatological, hepatic, cardiovascular, respiratory, neurological, seizure, allergy conditions) among amphetamine users. After adjusting for demographic variables and lifetime use of other substances: current amphetamine users and former injectors showed an increased likelihood of having medical illnesses and hospitalizations; current injectors had elevated odds of suicidal thoughts or attempts; current noninjectors exhibited elevated odds of anxiety, cognitive impairment, and violent behaviors; and former noninjectors had increased odds of depression.
Conclusion
Treatment-seeking, amphetamine-using, opioid-dependent adults manifest greater levels of medical and psychiatric morbidity than treatment-seeking, opioid-dependent adults who have not used amphetamines, indicating a greater need for intensive clinical management.
doi:10.2147/SAR.S20895
PMCID: PMC3163455  PMID: 21886430
amphetamine use; buprenorphine; clinical trials network; injection drug use; methamphetamine use; opioid dependence; rehabilitation
23.  Co-occurring amphetamine use and associated medical and psychiatric comorbidity among opioid-dependent adults: results from the clinical Trials Network 
Background
In response to the rising rate of treatment admissions related to illicit use of amphetamines (eg, methamphetamine), we examined the prevalence of amphetamine use among treatment-seeking, opioid-dependent adults, explored whether amphetamine users were as likely as nonamphetamine users to enroll in opioid-dependence treatment trials, and determined whether amphetamine users manifested greater levels of medical and psychiatric comorbidity than nonusers.
Methods
The sample included 1257 opioid-dependent adults screened for participation in three-multisite studies of the National Drug Abuse Treatment Clinical Trials Network (CTN001-003), which studied the effectiveness of buprenorphine for opioid detoxification under varying treatment conditions. Patients were recruited from 23 addiction treatment programs across the US. Medical and psychiatric comorbidity were examined by past-month amphetamine use (current vs former) and route of administration. Five mutually exclusive groups were examined, ie, nonusers, current amphetamine injectors, current amphetamine noninjectors, former amphetamine injectors, and former amphetamine noninjectors.
Results
Of the sample (n = 1257), 22.3% had a history of regular amphetamine use. Of the 280 amphetamine users, 30.3% reported injection as their primary route. Amphetamine users were more likely than nonusers to be white and use more substances. Amphetamine users were as likely as nonusers to enroll in treatment trials. Bivariate analyses indicated elevated rates of psychiatric problems (depression, anxiety, hallucinations, cognitive impairment, violence, suicidal thoughts/attempts) and medical illnesses (dermatological, hepatic, cardiovascular, respiratory, neurological, seizure, allergy conditions) among amphetamine users. After adjusting for demographic variables and lifetime use of other substances: current amphetamine users and former injectors showed an increased likelihood of having medical illnesses and hospitalizations; current injectors had elevated odds of suicidal thoughts or attempts; current noninjectors exhibited elevated odds of anxiety, cognitive impairment, and violent behaviors; and former noninjectors had increased odds of depression.
Conclusion
Treatment-seeking, amphetamine-using, opioid-dependent adults manifest greater levels of medical and psychiatric morbidity than treatment-seeking, opioid-dependent adults who have not used amphetamines, indicating a greater need for intensive clinical management.
doi:10.2147/SAR.S20895
PMCID: PMC3163455  PMID: 21886430
amphetamine use; buprenorphine; clinical trials network; injection drug use; methamphetamine use; opioid dependence; rehabilitation
24.  Opioid Addiction and Pregnancy: Perinatal Exposure to Buprenorphine Affects Myelination in the Developing Brain 
Glia  2008;56(9):1017-1027.
Buprenorphine is a μ-opioid receptor partial agonist and κ-opioid receptor antagonist currently on trials for the management of pregnant opioid-dependent addicts. However, little is known about the effects of buprenorphine on brain development. Oligodendrocytes express opioid receptors in a developmentally regulated manner and thus, it is logical to hypothesize that perinatal exposure to buprenorphine could affect myelination. To investigate this possibility, pregnant rats were implanted with minipumps to deliver buprenorphine at 0.3 or 1 mg/kg/day. Analysis of their pups at different postnatal ages indicated that exposure to 0.3 mg/kg/day buprenorphine caused an accelerated and significant increase in the brain expression of all myelin basic protein (MBP) splicing isoforms. In contrast, treatment with the higher dose caused a developmental delay in MBP expression. Examination of corpus callosum at 26-days of age indicated that both buprenorphine doses cause a significant increase in the caliber of the myelinated axons. Surprisingly, these axons have a disproportionately thinner myelin sheath, suggesting alterations at the level of axon-glial interactions. Analysis of myelin associated glycoprotein (MAG) expression and glycosylation indicated that this molecule may play a crucial role in mediating these effects. Co-immunoprecipitation studies also suggested a mechanism involving a MAG-dependent activation of the Src-family tyrosine kinase Fyn. These results support the idea that opioid signaling plays an important role in regulating myelination in vivo and stress the need for further studies investigating potential effects of perinatal buprenorphine exposure on brain development.
doi:10.1002/glia.20675
PMCID: PMC2577583  PMID: 18381654
myelin synthesis; oligodendrocytes; opioids; buprenorphine
25.  Methadone, Buprenorphine, and Street Drug Interactions with Antiretroviral Medications 
Current HIV/AIDS Reports  2010;7(3):152-160.
While street drugs appear unlikely to alter the metabolism of antiretroviral (ARV) medications, several ARVs may induce or inhibit metabolism of various street drugs. However, research on these interactions is limited. Case reports have documented life-threatening overdoses of ecstasy and gamma-hydroxybutyrate after starting ritonavir, an ARV that inhibits several metabolic enzymes. For opioid addiction, methadone or buprenorphine are the treatments of choice. Because a number of ARVs decrease or increase methadone levels, patients should be monitored for methadone withdrawal or toxicity when they start or stop ARVs. Most ARVs do not cause buprenorphine withdrawal or toxicity, even if they alter buprenorphine levels, with rare exceptions to date including atazanavir/ritonavir associated with significant increases in buprenorphine and adverse events related to sedation and mental status changes in some cases. There are newer medications yet to be studied with methadone or buprenorphine. Further, there are many frequently used medications in treatment of complications of HIV disease that have not been studied. There is need for continuing research to define these drug interactions and their clinical significance.
doi:10.1007/s11904-010-0048-2
PMCID: PMC2892618  PMID: 20532839
Drug interactions; Street drugs; Methadone; Buprenorphine; Anti-HIV agents

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