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1.  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
2.  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
3.  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
4.  Canadian guideline for safe and effective use of opioids for chronic noncancer pain 
Canadian Family Physician  2011;57(11):1269-1276.
Abstract
Objective
To provide family physicians with a practical clinical summary of opioid prescribing for specific populations based on recommendations from the Canadian Guideline for Safe and Effective Use of Opioids for Chronic Non-Cancer Pain.
Quality of evidence
Researchers for the guideline conducted a systematic review of the literature, focusing on reviews of the effectiveness and safety of opioids in specific populations.
Main message
Family physicians can minimize the risks of overdose, sedation, misuse, and addiction through the use of strategies tailored to the age and health status of patients. For patients at high risk of addiction, opioids should be reserved for well-defined nociceptive or neuropathic pain conditions that have not responded to first-line treatments. Opioids should be titrated slowly, with frequent dispensing and close monitoring for signs of misuse. Suspected opioid addiction is managed with structured opioid therapy, methadone or buprenorphine treatment, or abstinence-based treatment. Patients with mood and anxiety disorders tend to have a blunted analgesic response to opioids, are at higher risk of misuse, and are often taking sedating drugs that interact adversely with opioids. Precautions similar to those for other high-risk patients should be employed. The opioid should be tapered if the patient’s pain remains severe despite an adequate trial of opioid therapy. In the elderly, sedation, falls, and overdose can be minimized through lower initial doses, slower titration, benzodiazepine tapering, and careful patient education. For pregnant women taking daily opioid therapy, the opioids should be slowly tapered and discontinued. If this is not possible, they should be tapered to the lowest effective dose. Opioid-dependent pregnant women should receive methadone treatment. Adolescents are at high risk of opioid overdose, misuse, and addiction. Patients with adolescents living at home should store their opioid medication safely. Adolescents rarely require long-term opioid therapy.
Conclusion
Family physicians must take into consideration the patient’s age, psychiatric status, level of risk of addiction, and other factors when prescribing opioids for chronic pain.
PMCID: PMC3215603  PMID: 22084456
5.  Prior buprenorphine experience is associated with office-based buprenorphine treatment outcomes 
Journal of addiction medicine  2013;7(4):287-293.
Objectives
As buprenorphine treatment and illicit buprenorphine use increase, many patients seeking buprenorphine treatment will have had prior experience with buprenorphine. Little evidence is available to guide optimal treatment strategies for patients with prior buprenorphine experience. We examined whether prior buprenorphine experience was associated with treatment retention and opioid use. We also explored whether type of prior buprenorphine use (prescribed or illicit use) was associated with these treatment outcomes.
Methods
We analyzed interview and medical record data from a longitudinal cohort study of 87 individuals who initiated office-based buprenorphine treatment. We examined associations between prior buprenorphine experience and 6-month treatment retention using logistic regression models, and prior buprenorphine experience and any self-reported opioid use at 1, 3, and 6 months using non-linear mixed models.
Results
Most (57.4%) participants reported prior buprenorphine experience; of these, 40% used prescribed buprenorphine and 60% illicit buprenorphine only. Compared to buprenorphine-naïve participants, those with prior buprenorphine experience had better treatment retention (AOR=2.65, 95% CI=1.05–6.70). Similar associations that did not reach significance were found when exploring prescribed and illicit buprenorphine use. There was no difference in opioid use when comparing participants with prior buprenorphine experience to those who were buprenorphine-naive (AOR=1.33, 95% CI=0.38–4.65). Although not significant, qualitatively different results were found when exploring opioid use by type of prior buprenorphine use (prescribed buprenorphine vs. buprenorphine-naïve, AOR=2.20, 95% CI=0.58–8.26; illicit buprenorphine vs. buprenorphine-naïve, AOR=0.47, 95% CI=0.07–3.46).
Conclusions
Prior buprenorphine experience was common and associated with better retention. Understanding how prior buprenorphine experience affects treatment outcomes has important clinical and public health implications.
doi:10.1097/ADM.0b013e31829727b2
PMCID: PMC3737355  PMID: 23722632
buprenorphine; opioid; opioid dependence; office-based treatment
6.  Costs of care for persons with opioid dependence in commercial integrated health systems 
Background
When used in general medical practices, buprenorphine is an effective treatment for opioid dependence, yet little is known about how use of buprenorphine affects the utilization and cost of health care in commercial health systems.
Methods
The objective of this retrospective cohort study was to examine how buprenorphine affects patterns of medical care, addiction medicine services, and costs from the health system perspective. Individuals with two or more opioid-dependence diagnoses per year, in two large health systems (System A: n = 1836; System B: n = 4204) over the time span 2007–2008 were included. Propensity scores were used to help adjust for group differences.
Results
Patients receiving buprenorphine plus addiction counseling had significantly lower total health care costs than patients with little or no addiction treatment (mean health care costs with buprenorphine treatment = $13,578; vs. mean health care costs with no addiction treatment = $31,055; p < .0001), while those receiving buprenorphine plus addiction counseling and those with addiction counseling only did not differ significantly in total health care costs (mean costs with counseling only: $17,017; p = .5897). In comparison to patients receiving buprenorphine plus counseling, those with little or no addiction treatment had significantly greater use of primary care (p < .001), other medical visits (p = .001), and emergency services (p = .020). Patients with counseling only (compared to patients with buprenorphine plus counseling) used less inpatient detoxification (p < .001), and had significantly more PC visits (p = .001), other medical visits (p = .005), and mental health visits (p = .002).
Conclusions
Buprenorphine is a viable alternative to other treatment approaches for opioid dependence in commercial integrated health systems, with total costs of health care similar to abstinence-based counseling. Patients with buprenorphine plus counseling had reduced use of general medical services compared to the alternatives.
doi:10.1186/1940-0640-9-16
PMCID: PMC4142137  PMID: 25123823
Substance abuse; Cost analysis; Health care utilization; Commercial health insurance; Parity
7.  Predictors of Outcome for Short-Term Medically Supervised Opioid Withdrawal during a Randomized, Multi Center Trial of Buprenorphine-Naloxone and Clonidine in the NIDA Clinical Trials Network Drug and Alcohol Dependence 
Drug and alcohol dependence  2008;99(1-3):28-36.
Few studies in community settings have evaluated predictors, mediators, and moderators of treatment success for medically supervised opioid withdrawal treatment. This report presents new findings about these factors from a study of 344 opioid dependent men and women prospectively randomized to either buprenorphine-naloxone or clonidine in an open-label 13-day medically-supervised withdrawal study. Subjects were either inpatient or outpatient in community treatment settings; however not randomized by treatment setting. Medication type (buprenorphine-naloxone versus clonidine) was the single best predictor of treatment retention and treatment success, regardless of treatment setting. Compared to the outpatient setting, the inpatient setting was associated with higher abstinence rates but similar retention rates when adjusting for medication type. Early opioid withdrawal severity mediated the relationship between medication type and treatment outcome with buprenorphine-naloxone being superior to clonidine at relieving early withdrawal symptoms. Inpatient subjects on clonidine with lower withdrawal scores at baseline did better than those with higher withdrawal scores; inpatient subjects receiving buprenorphine-naloxone did better with higher withdrawal scores at baseline than those with lower withdrawal scores. No relationship was found between treatment outcome and age, gender, race, education, employment, marital status, legal problems, baseline depression, or length/severity of drug use. Tobacco use was associated with worse opioid treatment outcomes. Severe baseline anxiety symptoms doubled treatment success. Medication type (buprenorphine-naloxone) was the most important predictor of positive outcome; however the paper also considers other clinical and policy implications of other results, including that inpatient setting predicted better outcomes and moderated medication outcomes.
doi:10.1016/j.drugalcdep.2008.06.016
PMCID: PMC2770269  PMID: 18805656
8.  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
9.  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
10.  Neonatal Abstinence Syndrome after Methadone or Buprenorphine Exposure 
The New England journal of medicine  2010;363(24):2320-2331.
BACKGROUND
Methadone, a full mu-opioid agonist, is the recommended treatment for opioid dependence during pregnancy. However, prenatal exposure to methadone is associated with a neonatal abstinence syndrome (NAS) characterized by central nervous system hyperirritability and autonomic nervous system dysfunction, which often requires medication and extended hospitalization. Buprenorphine, a partial mu-opioid agonist, is an alternative treatment for opioid dependence but has not been extensively studied in pregnancy.
METHODS
We conducted a double-blind, double-dummy, flexible-dosing, randomized, controlled study in which buprenorphine and methadone were compared for use in the comprehensive care of 175 pregnant women with opioid dependency at eight international sites. Primary outcomes were the number of neonates requiring treatment for NAS, the peak NAS score, the total amount of morphine needed to treat NAS, the length of the hospital stay for neonates, and neonatal head circumference.
RESULTS
Treatment was discontinued by 16 of the 89 women in the methadone group (18%) and 28 of the 86 women in the buprenorphine group (33%). A comparison of the 131 neonates whose mothers were followed to the end of pregnancy according to treatment group (with 58 exposed to buprenorphine and 73 exposed to methadone) showed that the former group required significantly less morphine (mean dose, 1.1 mg vs. 10.4 mg; P<0.0091), had a significantly shorter hospital stay (10.0 days vs. 17.5 days, P<0.0091), and had a significantly shorter duration of treatment for the neonatal abstinence syndrome (4.1 days vs. 9.9 days, P<0.003125) (P values calculated in accordance with prespecified thresholds for significance). There were no significant differences between groups in other primary or secondary outcomes or in the rates of maternal or neonatal adverse events.
CONCLUSIONS
These results are consistent with the use of buprenorphine as an acceptable treatment for opioid dependence in pregnant women. (Funded by the National Institute on Drug Abuse; ClinicalTrials.gov number, NCT00271219.)
doi:10.1056/NEJMoa1005359
PMCID: PMC3073631  PMID: 21142534
11.  Opioid Dependency in Pregnancy and Length of Stay for Neonatal Abstinence Syndrome 
Objective
To examine opioid replacement therapy in pregnancy and maternal effects on neonatal outcomes including length of hospital stay for neonatal abstinence syndrome.
Design
Retrospective descriptive study.
Setting
Labor and Delivery Unit and Neonatal Intensive Care Unit (NICU), Eastern Maine Medical Center, Bangor, Maine.
Participants
One hundred fifty two opioid dependent pregnant women on methadone maintenance therapy (MMT) (n = 136) or buprenorphine maintenance therapy (BMT) (n =16) during pregnancy and their neonates. The neonates were born between January 1, 2005 and December 31, 2007.
Methods
A review of the electronic medical records (EMR) was conducted of all opioid dependent women who were maintained on MMT or BMT at the time of admission for labor and delivery and their neonates.
Results
Maternal methadone dose and concomitant in-utero exposure to benzodiazepines prolonged the length of hospital stay for neonates. Length of stay was shorter in breastfed neonates as compared to formula fed neonates or neonates who received formula and breast milk. Neonates with a prenatal exposure to MMT as compared to BMT spent more days in the hospital (21 vs. 14 days) for treatment of neonatal abstinence syndrome (NAS).
Conclusion
These findings are consistent with previous research on the simultaneous use of methadone and benzodiazepines during pregnancy and provide further direction for the treatment of opioid dependency during pregnancy. Harm reduction strategies for opioid dependent pregnant women in substance abuse treatment with MMT may one day include guidance on daily treatment doses and recommendations to avoid the concomitant use of benzodiazepines to lessen NAS. Breastfeeding should be recommended to shorten LOS. Understanding perinatal and neonatal outcomes of pregnant women on methadone or buprenorphine will help to identify optimal treatment for opioid dependency in pregnancy.
doi:10.1111/j.1552-6909.2011.01330.x
PMCID: PMC3407283  PMID: 22375882
Opioid dependency; neonatal abstinence syndrome; methadone maintenance therapy; buprenorphine maintenance therapy; selective serotonin reuptake inhibitors; benzodiazepines; neonatal length of stay; breastfeeding
12.  Neonatal Outcomes and their Relationship to Maternal Buprenorphine Dose during Pregnancy 
Drug and alcohol dependence  2013;134:414-417.
Background
Buprenorphine pharmacotherapy for opioid-dependent pregnant women is associated with maternal and neonatal outcomes superior to untreated opioid dependence. However, the literature is inconsistent regarding the possible existence of a dose-response relationship between maternal buprenorphine dose and neonatal clinical outcomes.
Methods
The present secondary analysis study (1) examined the relationship between maternal buprenorphine dose at delivery and neonatal abstinence syndrome (NAS) peak score, estimated gestational age at delivery, Apgar scores at 1 and 5 minutes, neonatal head circumference, length, and weight at birth, amount of morphine needed to treat NAS, duration of NAS treatment, and duration of neonatal hospital stay; and (2) compared neonates who required pharmacotherapy for NAS to neonates who did not require such pharmacotherapy on these same outcomes, in 58 opioid-dependent pregnant women receiving buprenorphine as participants in a randomized clinical trial.
Results
(1) Analyses failed to provide evidence of a relationship between maternal buprenorphine dose at delivery and any of the 10 outcomes (all p-values>.48); and (2) significant mean differences between the untreated (n=31) and treated (n=27) for NAS groups were found for duration of neonatal hospital stay and NAS peak score (both p-values<.001).
Conclusions
(1) Findings failed to support the existence of a dose-response relationship between maternal buprenorphine dose at delivery and any of 10 neonatal clinical outcomes, including NAS severity; and (2) that infants treated for NAS had a higher mean NAS peak score and, spent a longer time in the hospital than did the group not treated for NAS is unsurprising.
doi:10.1016/j.drugalcdep.2013.11.006
PMCID: PMC4117648  PMID: 24290979
opioid use disorder; pregnancy; buprenorphine; neonate; neonatal abstinence syndrome
13.  Opioid dependence 
Clinical Evidence  2011;2011:1015.
Introduction
Dependence on opioids is a multifactorial condition involving genetic and psychosocial factors. There are three stages to treating opioid dependence. Stabilisation is usually by opioid substitution treatments, and aims to ensure that the drug use becomes independent of mental state (such as craving and mood) and independent of circumstances (such as finance and physical location). The next stage is to withdraw (detox) from opioids. The final stage is relapse prevention. This treatment process contributes to recovery of the individual, which also includes improved overall health and wellbeing, as well as engagement in society.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments for stabilisation (maintenance) in people with opioid dependence? What are the effects of drug treatments for withdrawal in people with opioid dependence? What are the effects of drug treatments for relapse prevention in people with opioid dependence? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2011 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 26 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: buprenorphine; clonidine; lofexidine; methadone; naltrexone; and ultra-rapid withdrawal regimens.
Key Points
Dependence on opioids is a multifactorial condition involving genetic and psychosocial factors.
There are three stages to treating opioid dependence. Stabilisation is usually by opioid substitution treatments, and aims to ensure that the drug use becomes independent of mental state (such as craving and mood) and independent of circumstances (such as finance and physical location).The next stage is to withdraw (detox) from opioids.The final stage is relapse prevention.
Methadone and buprenorphine help to stabilise opioid use, as they decrease heroin use and help to retain people in treatment programmes. Methadone and buprenorphine seem equally effective at stabilising opioid use.
Methadone, buprenorphine, and alpha2-adrenoceptor agonists (lofexidine, clonidine) can all help people to withdraw from dependence on illicit opioids. Lofexidine and clonidine may be less effective than methadone and buprenorphine in withdrawal, although evidence is weak. Ultra-rapid withdrawal can help in detoxification, although there are important safety risks in keeping people heavily sedated or under general anaesthesia for a day, or under general anaesthesia for a few hours, and outcomes are no better.
Naltrexone can help to prevent relapse of heroin use if combined with psychosocial treatment.
PMCID: PMC3275107  PMID: 21929827
14.  Treatment Retention among Patients Randomized to Buprenorphine/Naloxone Compared to Methadone in A Multi-site Trial 
Addiction (Abingdon, England)  2013;109(1):79-87.
Aims
To examine patient and medication characteristics associated with retention and continued illicit opioid use in methadone (MET) versus buprenorphine/naloxone (BUP) treatment for opioid dependence.
Design/Settings/Participants
This secondary analysis included 1,267 opioid-dependent individuals participating in 9 opioid treatment programs between 2006 and 2009 and randomized to receive open-label BUP or MET for 24 weeks.
Measurements
The analyses included measures of patient characteristics at baseline (demographics; use of alcohol, cigarettes, and illicit drugs; self-rated mental and physical health), medication dose and urine drug screens during treatment, and treatment completion and days in treatment during the 24 week trial.
Findings
The treatment completion rate was 74% for MET vs. 46% for BUP (p<.01); the rate among MET participants increased to 80% when the maximum MET dose reached or exceeded 60mg/day. With BUP, the completion rate increased linearly with higher doses, reaching 60% with doses of 30–32mg/day. Of those remaining in treatment, positive opioid urine results were significantly lower (OR=0.63, 95%CI=0.52–0.76, p<.01) among BUP relative to MET participants during the first 9 weeks of treatment. Higher medication dose was related to lower opiate use, more so among BUP patients. A Cox proportional hazards model revealed factors associated with dropout: (1) BUP (vs. MET, HR=1.61, CI:1.20–2.15), (2) lower medication dose (<16mg for BUP, <60mg for MET; HR=3.09, CI:2.19–4.37), (3) the interaction of dose and treatment condition (those with higher BUP dose were 1.04 times more likely to drop out than those with lower MET dose, and (4) being younger, Hispanic, and using heroin or other substances during treatment.
Conclusions
Provision of methadone appears to be associated with better retention in treatment for opioid dependence than buprenorphine, as does use of provision of higher doses of both medications. Provision of buprenorphine is associated with lower continued use of illicit opioids.
doi:10.1111/add.12333
PMCID: PMC3947022  PMID: 23961726
15.  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
16.  Buprenorphine Treatment Outcomes among Opioid-Dependent Cocaine Users and Non-users 
Background and Objectives
National treatment guidelines state that polysubstance users, including cocaine users, may not be appropriate candidates for office-based buprenorphine treatment. However, data to support this recommendation are sparse and conflicting, and the implications of this recommendation may include limiting the usefulness of buprenorphine treatment, as cocaine use is common among opioid-dependent individuals seeking buprenorphine treatment. We compared buprenorphine treatment outcomes (6-month treatment retention and self-reported opioid use over 6 months) in opioid-dependent cocaine users versus non-users who initiated buprenorphine treatment at an urban community health center.
Methods
We followed 87 participants over 6 months, collecting interview and medical record data. We used logistic regression models to test whether baseline cocaine use was associated with treatment retention and mixed effects non-linear models to test whether baseline cocaine use was associated with self-reported opioid use.
Results
At baseline, 39.1% reported cocaine use. In all participants, self-reported opioid use decreased from 89.7% to 27.4% over 6 months, and 6-month treatment retention was 54.5%. We found no significant difference in 6-month treatment retention (AOR=1.56, 95%CI=0.58–4.17, p=0.38) or self-reported opioid use (AOR=0.89, 95%CI=0.26–3.07, p=0.85) between cocaine users and non-users.
Conclusions and Scientific Significance
This study demonstrates that buprenorphine treatment retention is not worse in cocaine users than non-users, with clinically meaningful improvements in self-reported opioid use. These findings suggest that opioid-dependent cocaine users attain considerable benefits from office-based buprenorphine treatment and argue for the inclusion of these patients in office-based buprenorphine treatment programs.
doi:10.1111/j.1521-0391.2013.12032.x
PMCID: PMC3694744  PMID: 23795874
17.  Testing use of payers to facilitate evidence-based practice adoption: protocol for a cluster-randomized trial 
Background
More effective methods are needed to implement evidence-based findings into practice. The Advancing Recovery Framework offers a multi-level approach to evidence-based practice implementation by aligning purchasing and regulatory policies at the payer level with organizational change strategies at the organizational level.
Methods
The Advancing Recovery Buprenorphine Implementation Study is a cluster-randomized controlled trial designed to increase use of the evidence-based practice buprenorphine medication to treat opiate addiction. Ohio Alcohol, Drug Addiction, and Mental Health Services Boards (ADAMHS), who are payers, and their addiction treatment organizations were recruited for a trial to assess the effects of payer and treatment organization changes (using the Advancing Recovery Framework) versus treatment organization changes alone on the use of buprenorphine. A matched-pair randomization, based on county characteristics, was applied, resulting in seven county ADAMHS boards and twenty-five treatment organizations in each arm. Opioid dependent patients are nested within cluster (treatment organization), and treatment organization clusters are nested within ADAMHS county board. The primary outcome is the percentage of individuals with an opioid dependence diagnosis who use buprenorphine during the 24-month intervention period and the 12-month sustainability period. The trial is currently in the baseline data collection stage.
Discussion
Although addiction treatment providers are under increasing pressure to implement evidence-based practices that have been proven to improve patient outcomes, adoption of these practices lags, compared to other areas of healthcare. Reasons frequently cited for the slow adoption of EBPs in addiction treatment include, regulatory issues, staff, or client resistance and lack of resources. Yet the way addiction treatment is funded, the payer’s role—has not received a lot of attention in research on EBP adoption.
This research is unique because it investigates the role of payers in evidence-based practice implementation using a randomized controlled design instead of case examples. The testing of the Advancing Recovery Framework is designed to broaden the understanding of the impact payers have on evidence-based practice (EBP) adoption.
Trial registration
http://NCT01702142 (ClinicalTrials.gov registry, USA)
doi:10.1186/1748-5908-8-50
PMCID: PMC3666944  PMID: 23663749
Evidence-based practice implementation; Buprenorphine; Addiction treatment; Innovation
18.  Maternal Buprenorphine Dose, Placenta Buprenorphine and Metabolite Concentrations and Neonatal Outcomes 
Therapeutic drug monitoring  2010;32(2):206-215.
Buprenorphine is approved as pharmacotherapy for opioid dependence in non-pregnant patients in multiple countries, and is currently under investigation for pregnant women in the US and Europe. This research evaluates the disposition of buprenorphine, opiates, cocaine, and metabolites in 5 term placentas from a US cohort. Placenta and matched meconium concentrations were compared, and relationships between maternal buprenorphine dose, placenta concentrations, and neonatal outcomes following controlled administration during gestation were investigated. Buprenorphine and/or metabolites were detected in all placenta specimens and were uniformly distributed across this tissue (CV<27.5%, 4 locations), except for buprenorphine in 3 placentas. In 2 of these, buprenorphine was not detected in some locations and, in the 3rd placenta, was totally absent. Median (range) concentrations were buprenorphine 1.6ng/g (not detected to 3.2), norbuprenorphine 14.9ng/g (6.2 to 24.2), buprenorphine-glucuronide 3ng/g (1.3 to 5.0) and norbuprenorphine-glucuronide 14.7ng/g (11.4 to 25.8). Placenta is a potential alternative matrix for detecting in utero buprenorphine exposure, but at lower concentrations (15–70 fold) than in meconium. Statistically significant correlations were observed for mean maternal daily dose from enrollment to delivery and placenta buprenorphine-glucuronide concentration, and for norbuprenorphine-glucuronide concentrations and time to neonatal abstinence syndrome (NAS) onset and duration, and for norbuprenorphine/norbuprenorphine-glucuronide ratio and maximum NAS score, and newborn length. Analysis of buprenorphine and metabolites in this alternative matrix, an abundant waste product available at the time of delivery, may be valuable for prediction of neonatal outcomes for clinicians treating newborns of buprenorphine-exposed women.
doi:10.1097/FTD.0b013e3181d0bd68
PMCID: PMC2921577  PMID: 20216119
buprenorphine; placenta; Neonatal Abstinence Syndrome; in utero drug exposure; opioid-dependence
19.  Drug Treatment Outcomes among HIV-Infected Opioid Dependent Patients Receiving Buprenorphine/naloxone 
Journal of acquired immune deficiency syndromes (1999)  2011;56(0 1):10.1097/QAI.0b013e3182097537.
Background
Buprenorphine/naloxone allows the integration of opioid dependence and HIV treatment.
Methods
We conducted a prospective study in HIV-infected opioid dependent patients to investigate the impact of buprenorphine/naloxone treatment on drug use. Self-report and chart review assessments were conducted every 3 months (Quarters 1 through 4) for one year. Outcomes were buprenorphine/naloxone treatment retention, drug use, and addiction treatment processes.
Results
Among 303 patients enrolled between July 2005 and December 2007, retention in buprenorphine/naloxone treatment was 74%, 67%, 59% and 49% during Quarters 1,2 3, and 4, respectively. Past 30 day illicit opioid use decreased from 84% of patients at baseline to 42% in retained patients over the year. Patients were 52% less likely to use illicit opioids for each quarter in treatment (OR = .66; 95% CI 0.61–0.72). Buprenorphine/naloxone doses and office visits approximated guidelines published by the United States Department of Health and Human Services. Urine toxicology monitoring was less frequent than recommended.
Conclusions
Buprenorphine/naloxone provided in HIV treatment settings can decrease opioid use. Strategies are needed to improve retention and address ongoing drug use in this treatment population.
doi:10.1097/QAI.0b013e3182097537
PMCID: PMC3863630  PMID: 21317592
Buprenorphine; heroin dependence; opioid-related disorders; HIV; methadone
20.  Heroin Dependence Treatment in Malaysia: A randomized, double-blind placebo-controlled comparison of buprenorphine and naltrexone maintenance treatment 
Lancet  2008;371(9631):2192-2200.
Background
Expanding access to effective treatments for heroin dependence is a global health priority that will also reduce HIV transmission. This study compares the efficacy for maintaining heroin abstinence, preventing relapse, and reducing HIV risk behaviors of three common treatments: detoxification followed by drug counseling only or drug counseling combined with opioid antagonist (naltrexone) or agonist (buprenorphine) maintenance treatment.
Methods
126 detoxified heroin dependent patients in Malaysia were randomly assigned to 24 weeks of medication maintenance with naltrexone, buprenorphine, or placebo, provided double-blind and double-dummy. All patients received manual-guided drug counseling. Primary outcomes, assessed by three times per week urine testing, were days to first heroin use, days to heroin relapse (3 consecutive opioid-positive urine tests), maximum consecutive days heroin abstinence, and, assessed by self-report at baseline, 3- and 6-months, reductions in HIV risk behaviors. The study was terminated after 22 months of enrolment, based on findings of superior buprenorphine efficacy in an interim safety analysis and the recommendation of the Data and Safety Monitoring Board. This study is registered with ClinicalTrials.gov, with the number NCT00383045.
Findings
We observed consistent, significant linear contrasts in days to first heroin use (p<0.001), days to heroin relapse (p<0.001), maximum consecutive days heroin abstinence (p<0.01), and retention (p<0.001), with all results best for buprenorphine, intermediate for naltrexone, and worst for placebo. Buprenorphine was associated with significantly greater time to first heroin use and retention compared to naltrexone (p<0.01 for both measures) or placebo (p<0.001 for both measures) and also significantly greater time to heroin relapse (p<0.01) and maximum consecutive weeks abstinent (p<0.01) compared to placebo. There were no significant differences between naltrexone and placebo on these measures. HIV risk behaviors were significantly reduced from baseline across all 3 treatments (p<0.001), but the reductions did not differ significantly among the 3 treatments.
Interpretation
The effectiveness of buprenorphine for maintaining prolonged periods of abstinence, delaying the time to resumption of heroin use or relapse, and retaining patients in treatment supports widespread dissemination of opioid agonist maintenance treatment.
doi:10.1016/S0140-6736(08)60954-X
PMCID: PMC4041792  PMID: 18586174
Heroin Dependence; Buprenorphine; Naltrexone; Randomized Clinical Trial; HIV/AIDS
21.  Management of opioid addiction with buprenorphine: French history and current management 
The way in which opioid addiction is managed in France is unique, as it is based on the prescription of buprenorphine by general practitioners and is dispensed by retail pharmacies. This policy has had a direct, positive impact on the number of deaths caused by heroin overdose, which was reduced by four-fifths between 1994 and 2002. In addition, certain associated comorbidities, such as infection with the human immunodeficiency virus, have also been reduced; the incidence of acquired immune deficiency syndrome in intravenous drug users fell from 25% in the mid-1990s to 6% in 2010. Since the implementation of this French model of opioid management, major scientific progress has been made, leading to a better understanding of the pathophysiologic mechanisms of addiction and of the management modalities required for its treatment. However, despite notable advances in scientific knowledge and in the implementation of devices, opioid addiction remains a major public health care issue in France, with 275,000–360,000 “problem drug users” being reported in 2011. The situation is still particularly worrying due to psychoactive substance use and misuse of opioid substitution treatments. Since 2003, there has been a persistent increase in the number of deaths and comorbidities related to opioid addiction, principally hepatitis C virus infection, which affects up to 40% of intravenous drug users. In France, the direct involvement of general practitioners in the management of opioid addiction is indisputable. Nevertheless, management could be optimized through better understanding of the pathophysiologic mechanisms of the disease, better knowledge of the pharmacology of opioid substitution treatments, and clear definition of short-, medium- and long-term treatment objectives. Data related to the management of opioid addiction by general practitioners in France have been published in 2005. Since then, the context has changed, other drugs were launched on the market such as generics of buprenorphine, methadone capsule, and Suboxone. Thus, an update seems necessary. This paper provides a description of opioid addiction management objectives and treatment modalities for general practitioners, based on currently available knowledge.
doi:10.2147/IJGM.S53170
PMCID: PMC3949694  PMID: 24623988
opioid addiction; withdrawal; opioid substitution treatment; buprenorphine; naloxone; general medicine
22.  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
23.  Prescription opioid abuse, pain and addiction: Clinical issues and implications 
Drug and alcohol review  2011;30(3):300-305.
Issues
Prescription opioid misuse in the USA has increased over threefold since 1990 to epidemic proportions, with substantial increases in prescription opioid use also reported in other countries, such as Australia and New Zealand. The broad availability of prescription pain medications, coupled with public misconceptions about their safety and addictive potential, have contributed to the recent surge in non-medical use of prescription opioids and corresponding increases in treatment admissions for problems related to opioid misuse. Given competing pressures faced by physicians to both diagnose and treat pain syndromes and identify individuals at risk for addictive disorders, the use of opioids in the treatment of pain poses a significant clinical challenge.
Approach
This paper reviews the interaction between pain and opioid addiction with a focus on clinical management issues, including risk factors for opioid dependence in patients with chronic pain and the use of assessment tools to identify and monitor at-risk individuals. Treatment options for opioid dependence and pain are reviewed, including the use of the partial μ agonist buprenorphine in the management of concurrent pain and opioid addiction.
Implications
Physicians should strive to find a reasonable balance between minimising potential adverse effects of opioid medications without diminishing legitimate access to opioids for analgesia.
Conclusions
The article discusses the need to identify methods for minimising risks and negative consequences associated with opioid analgesics and poses research directions, including the development of abuse-deterrent opioid formulations, genetic risk factors for opioid dependence and opioid-induced hyperalgesia as a potential target for medication therapy.
doi:10.1111/j.1465-3362.2010.00271.x
PMCID: PMC4170948  PMID: 21545561
pain management; opioid dependence; buprenorphine; addiction; medication
24.  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
25.  Predictors of buprenorphine-naloxone dosing in a 12-week treatment trial for opioid-dependent youth: Secondary analyses from a NIDA Clinical Trials Network study 
Drug and alcohol dependence  2009;107(2-3):253-256.
Introduction
The present investigation examines baseline patient characteristics to predict dosing of buprenorphine-naloxone, a promising treatment for opioid addiction in youths.
Methods
This study of 69 opioid-dependent youths is a secondary analysis of data collected during a National Institute on Drug Abuse (NIDA) Clinical Trials Network study. Outpatients aged 15-21 were randomized to a 12-week buprenorphine-naloxone dosing condition (including 4 weeks of taper). Predictors of dosing included sociodemographic characteristics (gender, race, age, and education), substance use (alcohol, cannabis, cocaine, and nicotine use), and clinical characteristics (pain and withdrawal severity).
Results
Most (75.4%) reported having either “some” (n=40, 58.0 %) or “extreme” (n=12, 17.4%) pain on enrollment. Maximum daily dose of buprenorphine-naloxone (19.7 mg) received by patients reporting “extreme” pain at baseline was significantly higher than the dose received by patients reporting “some” pain (15.0 mg) and those without pain (12.8 mg). In the adjusted analysis, only severity of pain and withdrawal significantly predicted dose. During the dosing period, there were no significant differences in opioid use, as measured by urinalysis, by level of pain.
Conclusion
These data suggest that the presence of pain predicts buprenorphine-naloxone dose levels in opioid-dependent youth, and that patients with pain have comparable opioid use outcomes to those without pain, but require higher buprenorphine-naloxone doses.
doi:10.1016/j.drugalcdep.2009.10.014
PMCID: PMC2821971  PMID: 19948382
Buprenorphine; Naloxone; Opioid dependence; Treatment; Dose

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