History of the discovery, development, and FDA-approval of buprenorphine medications for the treatment of opioid use disorder.

Buprenorphine-based medications were first approved by the United States Food and Drug Administration in 2002 for the treatment of opioid dependence, or opioid use disorder (OUD) as the condition is presently known. This regulatory milestone was the outcome of 36 years of research and development, which also led to the development and approval of several other new buprenorphine-based medications. In this short review, we first describe the discovery and early development stages of buprenorphine. Second, we review key steps that led to the development of buprenorphine as a drug product. Third, we explain the regulatory approval of several buprenorphine-based medications for the treatment of OUD. We also discuss these developments in the context of the evolution of regulations and policies that have progressively improved OUD treatment availability and efficacy, although challenges remain in removing system-level, provider-level, and local-level barriers to quality treatment, to integrating OUD treatment into routine care and other settings, to reducing disparities in access to treatment, and to optimizing person-centered outcomes.

Assessment of craving in opioid use disorder: Psychometric evaluation and predictive validity of the opioid craving VAS.

BACKGROUND: This work evaluated the psychometric properties of the single-item Opioid Craving Visual Analog Scale (OC-VAS) for opioid use disorder (OUD). METHODS: Psychometric evaluation of the OC-VAS (range: 0-100 mm) was supported by Subjective Opiate Withdrawal Scale (SOWS) item 16 and total score, Clinical Opiate Withdrawal Scale (COWS) scores, and the 36-Item Short-Form Health Survey, using data from phase 3 study (NCT02357901; N = 487) participants who received randomized treatment and completed the OC-VAS at screening. Descriptive properties, test-retest reliability, construct validity, known-groups validity, and responsiveness were assessed. Interpretation of meaningful change and predictive validity were also explored. RESULTS: Descriptive properties for the OC-VAS at screening did not provide evidence of problematic floor/ceiling effects or missingness. The test-retest reliability was established by weekly intraclass correlations >0.70. At the screening and end of the study, the strong positive correlations between OC-VAS and SOWS Total/Item 16 score and the significant OC-VAS differences among COWS severity groups supported construct validity and known-groups (discriminating ability) validity, respectively. The associations between the changes in OC-VAS and in supporting measures/opioid use from screening to the end of the study demonstrated responsiveness and the ability to detect change in clinical status. During the induction and randomization treatment periods, significant relationships were identified between OC-VAS score and subsequent opioid use. CONCLUSIONS: This psychometric evaluation of the OC-VAS performed on a large OUD patient population provides evidence to support its use to measure the severity of opioid craving and its ability to predict opioid use.

Treating Opioid Use Disorder With a Monthly Subcutaneous Buprenorphine Depot Injection: 12-Month Safety, Tolerability, and Efficacy Analysis.

BACKGROUND: BUP-XR (RBP-6000 or SUBLOCADE) is the first Food and Drug Administration-approved subcutaneously administered monthly extended-release buprenorphine medication for the treatment of moderate or severe opioid use disorder. The primary objective of this phase III study was to assess the long-term safety, tolerability, and efficacy of BUP-XR. METHODS: This open-label multicenter study in adults with moderate or severe opioid use disorder enrolled 257 participants from a previously conducted placebo-controlled, double-blind phase III study (rollover group) and 412 de novo participants not previously treated with BUP-XR. Participants received an initial injection of BUP-XR 300 mg and subsequent monthly 300 mg or 100 mg flexible doses. By study end, participants received up to 12 injections. RESULTS: Overall, 66.8% of participants reported more than 1 treatment-emergent adverse event (TEAE). Injection-site TEAEs (13.2% of participants) were mostly mild or moderate in severity. There were no clinically meaningful changes in safety assessments. An integrated analysis of the double-blind and open-label study participants showed that the incidence of TEAEs, including injection-site TEAEs, was lower in the second 6 months of treatment versus the first 6 months. After 12 months of treatment, 61.5% of the rollover participants and 75.8% of the de novo participants were abstinent. Retention rates after 12 months were 50.6% for the participants who initiated BUP-XR in the double-blind study and 50.5% for de novo participants. CONCLUSIONS: This study demonstrates that the clinical benefits and acceptable safety profile of BUP-XR demonstrated in the 6-month double-blind study are sustained over a 12-month open-label study, with lower incidence of TEAEs in the second 6 months of treatment.

Efficacy and safety of a monthly buprenorphine depot injection for opioid use disorder: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: RBP-6000, referred to as BUP-XR (extended-release buprenorphine), is a subcutaneously injected, monthly buprenorphine treatment for opioid use disorder. BUP-XR provides sustained buprenorphine plasma concentrations to block drug-liking of abused opioids over the entire monthly dosing period, while controlling withdrawal and craving symptoms. Administration of BUP-XR in a health-care setting also mitigates abuse, misuse, diversion, and unintentional exposure. We aimed to investigate the efficacy of different BUP-XR dosing regimens in participants with opioid use disorder. METHODS: This randomised, double-blind, placebo-controlled, phase 3 trial was done at 36 treatment centres in the USA. Treatment-seeking adults aged 18-65 years who had moderate or severe opioid use disorder (as defined by the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders) entered an open-label run-in phase of up to 2 weeks' treatment with buprenorphine-naloxone sublingual film. Eligible participants were then randomly assigned (4:4:1:1) with an interactive voice/web-response system to receive BUP-XR 300 mg/300 mg (six injections of 300 mg), BUP-XR 300 mg/100 mg (two injections of 300 mg plus four injections of 100 mg), or volume-matched placebo every 28 days, and received weekly individual drug counselling. No supplemental buprenorphine was allowed. The primary efficacy endpoint was participants' percentage abstinence from opioid use, defined as the percentage of each participant's negative urine samples and self-reports of illicit opioid use from week 5 to week 24, analysed in the full analysis set. Safety was assessed in all participants who received at least one dose of BUP-XR or placebo. This study is registered with ClinicalTrials.gov, number NCT02357901. FINDINGS: From Jan 28, 2015, to Nov 12, 2015, 1187 potential participants were screened, 665 entered run-in, and 504 received BUP-XR 300 mg/300 mg (n=201), BUP-XR 300 mg/100 mg (n=203), or placebo (n=100). Mean participants' percentage abstinence was 41·3% (SD 39·7) for BUP-XR 300 mg/300 mg and 42·7% (38·5) for 300 mg/100 mg, compared with 5·0% (17·0) for placebo (p<0·0001 for both BUP-XR regimens). No compensatory non-opioid drug use was observed during BUP-XR treatment. The most common adverse events were headache (17 [8%] participants in the BUP-XR 300 mg/300 mg group vs 19 [9%] participants in the BUP-XR 300 mg/100 mg group vs six [6%] participants in the placebo group), constipation (16 [8%] vs 19 [9%] vs 0), nausea (16 [8%] vs 18 [9%] vs five [5%]), and injection-site pruritis (19 [9%] vs 13 [6%] vs four [4%]). The BUP-XR safety profile was consistent with other buprenorphine products for treatment of opioid use disorder, except for injection-site reactions, which were reported in more than 5% of all participants who received BUP-XR, but were mostly mild and not treatment-limiting. INTERPRETATION: Participants' percentage abstinence was significantly higher in both BUP-XR groups than in the placebo group. Treatment with BUP-XR was also well tolerated. The availability of this monthly formulation, delivered by health-care providers, represents an advance in treatment for opioid use disorder that enhances the benefits of buprenorphine by delivering sustained, optimal exposure, while reducing risks of current buprenorphine products. FUNDING: Indivior.

Efficacy, Safety, and Tolerability of RBP-7000 Once-Monthly Risperidone for the Treatment of Acute Schizophrenia: An 8-Week, Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase 3 Study.

RBP-7000 is a sustained-release formulation of risperidone for the treatment of schizophrenia, designed to be administered by once-monthly subcutaneous injection using the ATRIGEL delivery system. This study assessed the efficacy, safety, and tolerability of RBP-7000 compared with placebo in subjects with acute exacerbation of schizophrenia. Inpatients were randomly assigned to 8 weeks of double-blind treatment with subcutaneous 90 or 120 mg of RBP-7000 or placebo. Efficacy was evaluated using a mixed-model repeated-measures analysis of the change from baseline (the last nonmissing value before the first dose of RBP-7000 or placebo on day 1) to end of the study in Positive and Negative Syndrome Scale (PANSS) total score (primary efficacy measure) and Clinical Global Impression-Severity score (secondary efficacy measure). The least-squares means from the repeated-measures analysis for the change from baseline in the PANSS total scores for placebo was -9.219 (SE, 1.2162). RBP-7000 produced statistically and clinically significant differences in mean reductions from baseline in PANSS total scores (90-mg RBP-7000 compared with placebo, -6.148 [-9.982 to -2.314], P = 0.0004; 120-mg RBP-7000 compared with placebo, -7.237 [-11.045 to -3.429], P < 0.0001) and significantly improved Clinical Global Impression-Severity scores (90-mg RBP-7000 compared with placebo, -0.350 [-0.557 to -0.143], P = 0.0002; 120-mg RBP-7000 compared with placebo, -0.396 [-0.602 to -0.190], P < 0.0001). Both RBP-7000 dosages were generally well tolerated. The most frequently reported treatment-emergent adverse events in RBP-7000 groups compared with placebo were somnolence, weight gain, and akathisia. The overall incidence of extrapyramidal syndrome-related effects was low and similar across groups. RBP-7000 may provide a new, long-acting alternative treatment for use in adults with acute schizophrenia.

Sustained-Release Buprenorphine (RBP-6000) Blocks the Effects of Opioid Challenge With Hydromorphone in Subjects With Opioid Use Disorder.

A major goal for the treatment of opioid use disorder is to reduce or eliminate the use of illicit opioids. Buprenorphine, a µ-opioid receptor partial agonist and kappa opioid receptor antagonist, is now being developed as a monthly, sustained-release formulation (RBP-6000). The objective of this study was to demonstrate that RBP-6000 blocks the subjective effects and reinforcing efficacy of the µ-opioid receptor agonist hydromorphone (intramuscularly administered) in subjects with moderate or severe opioid use disorder. Subjects were first inducted and dose stabilized on sublingual buprenorphine/naloxone (8-24 mg daily; dose expressed as the buprenorphine component), then received two subcutaneous injections of RBP-6000 (300 mg) on Day 1 and Day 29. Hydromorphone challenges (6 mg, 18 mg or placebo administered in randomized order) occurred on 3 consecutive days of each study week before and after receiving RBP-6000. Subjects reported their responses to each challenge on various 100-mm Visual Analogue Scales (VAS). Subjects also completed a choice task to assess the reinforcing efficacy of each hydromorphone dose relative to money. At baseline, mean "drug liking" VAS scores for hydromorphone 18 mg and 6 mg versus placebo were 61 mm (95% confidence interval, 52.3-68.9) and 45 mm (95% confidence interval, 37.2-53.6), respectively. After 300 mg RBP-6000 was administered, mean VAS score differences from placebo were less than 10 mm through week 12. The reinforcing efficacy of hydromorphone decreased in a parallel manner. This study demonstrated that RBP-6000 at a 300 mg dose provides durable and potent blockade of the subjective effects and reinforcing efficacy of hydromorphone in subjects with moderate or severe opioid use disorder.

Pharmacokinetics of Sublingual Buprenorphine and Naloxone in Subjects with Mild to Severe Hepatic Impairment (Child-Pugh Classes A, B, and C), in Hepatitis C Virus-Seropositive Subjects, and in Healthy Volunteers.

BACKGROUND AND OBJECTIVES: Suboxone(®) is a sublingual tablet of buprenorphine/naloxone, approved for the treatment of opioid dependence. The objective of this study was to quantify the impact of hepatic impairment or hepatitis C virus infection on the pharmacokinetics of buprenorphine or naloxone and their major metabolites. METHODS: Forty-three subjects received a single dose of a Suboxone 2.0/0.5-mg tablet. Blood samples were collected up to 168 h and pharmacokinetic parameters were calculated using non-compartmental analysis. Statistical analysis was performed using analysis of covariance. RESULTS: Pharmacokinetic parameters were derived from 33 subjects. Compared with healthy subjects, for patients with severe hepatic impairment, total and peak exposures increased to 281.4 % [90 % confidence interval 187.1-423.3] and 171.8 % [117.9-250.2] for buprenorphine, 1401.9 % [707.6-2777.5] and 1129.8 % [577.2-2211.4] for naloxone. For moderate hepatic impaired subjects, naloxone total and peak exposure increased to 317.6 % [164.9-611.5] and 270.0  % [141.9-513.9]. For buprenorphine, only total exposure increased to 163.9 % [110.8-242.3]. Changes in maximum observed plasma concentration, area under the plasma concentration-time curve from time zero to time of the last quantifiable concentration, and area under the plasma concentration-time curve from time zero to infinity of buprenorphine or naloxone in subjects with mild hepatic impairment or with hepatitis C virus infection were within twofold of those of healthy subjects. Serious adverse events were not observed. CONCLUSIONS: Severe and moderate hepatic impairment significantly increased exposure of naloxone and to a lesser extent of buprenorphine. Therefore, buprenorphine/naloxone combination products should generally be avoided in patients with severe hepatic impairment and may not be appropriate for patients with moderate hepatic impairment. However, buprenorphine/naloxone products may be used with caution for maintenance treatment in patients with moderate hepatic impairment who have initiated treatment on a buprenorphine product without naloxone [Registered at ClinicalTrials.gov as NCT01846455].

Population pharmacokinetic modeling and simulation to guide dose selection for RBP-7000, a new sustained-release formulation of risperidone.

RBP-7000 is a long-acting formulation of risperidone designed for once-monthly subcutaneous injection for the treatment of schizophrenia. The objective was to estimate clinically effective doses of RBP-7000 based on model simulations and on the comparison with other long-acting injectable antipsychotics. A population pharmacokinetic model of RBP-7000 was developed in 90 clinically stable schizophrenic patients having received single/repeated doses of 60, 90, or 120 mg. Model simulations were conducted to compare active moiety plasma exposure after repeated RBP-7000 administrations to the published data of long-acting risperidone injection (Risperdal® Consta®) at 25 and 50 mg, and of paliperidone palmitate (Invega® Sustenna®) at 50 and 100 mg equivalent paliperidone. Predictions of dopamine D2 receptor occupancy were derived from the simulated active moiety concentrations. Simulations showed similar active moiety plasma exposure at steady-state for 90 mg of RBP-7000 and 25 mg of long-acting risperidone. In comparison to risperidone, RBP-7000 reached effective concentrations immediately after the first administration. RBP-7000 at the doses of 60 and 90 mg provided similar active moiety plasma concentrations at steady-state compared to 50 and 100 mg equivalent paliperidone, respectively. These findings provide guidance for dose selection in Phase III clinical trials and suggest potential benefits for RBP-7000 over competitors.

A randomized, double-blind, placebo-controlled trial of RBP-8000 in cocaine abusers: pharmacokinetic profile of rbp-8000 and cocaine and effects of RBP-8000 on cocaine-induced physiological effects.

RBP-8000 is a double mutant cocaine esterase that rapidly metabolizes cocaine. This study was conducted to assess the pharmacokinetics of cocaine and cocaine-induced physiological effects in the absence (placebo) or presence of RBP-8000. Twenty-nine cocaine abusers were randomized 1:1 (active: placebo) to 4 sequences and 2 treatment periods. In the presence of RBP-8000, cocaine plasma exposures dropped by 90% within 2 min; cocaine-induced physiological effects were significantly reduced with higher extent and faster decrease in systolic blood pressure and pulse rate compared to placebo. This study provides strong evidence in support to use RBP-8000 as a pharmacotherapy for cocaine intoxication.

A population pharmacokinetic and pharmacodynamic modelling approach to support the clinical development of RBP-6000, a new, subcutaneously injectable, long-acting, sustained-release formulation of buprenorphine, for the treatment of opioid dependence.

BACKGROUND AND OBJECTIVES: This study implemented pharmacokinetic/pharmacodynamic modelling to support the clinical development of RBP-6000, a new, long-acting, sustained-release formulation of buprenorphine for the treatment of opioid dependence. Such a formulation could offer advantages over existing buprenorphine pharmacotherapy by improving patient compliance and reducing the diversion of the product. METHODS: A population pharmacokinetic model was developed using 36 opioid-dependent subjects who received single subcutaneous doses of RBP-6000. Another pharmacokinetic/pharmacodynamic model was developed using µ-opioid receptor occupancy (µORO) data to predict efficacy of RBP-6000 after repeated doses. It was also assessed how buprenorphine plasma concentrations were correlated with opioid withdrawal symptoms and hydromorphone agonist blockade data from 15 heroin-dependent subjects. RESULTS: The resulting pharmacokinetic model accurately described buprenorphine and norbuprenorphine plasma concentrations. A saturable maximum effect (E max) model with 0.67 ng/mL effective concentration at 50 % of maximum (EC50) and 91 % E max best described µORO versus buprenorphine plasma concentrations. Linear relationships were found among µORO, withdrawal symptoms and blockade of agonist effects. CONCLUSION: Previously published findings have demonstrated µORO ≥70 % is needed to achieve withdrawal suppression and blockade of opioid agonist subjective effects. Model simulations indicated that a 200 mg RBP-6000 dose should achieve 2­3 ng/mL buprenorphine average concentrations and desired efficacy.

Liquid chromatography/tandem mass spectrometry method for simultaneous determination of cocaine and its metabolite (-)ecgonine methyl ester in human acidified stabilized plasma samples.

Two simple, sensitive and rapid liquid chromatography/electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) methods (low range and high range) were developed and validated for the quantification of cocaine and its metabolite (-)ecgonine methyl ester (EME) in human acidified stabilized plasma samples. In the low range assay, cocaine and the internal standard, cocaine-D3, were extracted using a single step liquid-liquid extraction from human acidified stabilized plasma. For the high range assay, human acidified stabilized plasma containing cocaine, EME, and the internal standards, cocaine-D3 and EME-D3, was mixed with acetonitrile, and the protein precipitate was separated by centrifugation. Both cocaine and EME extracted from both assays were separated on a HILIC column and detected in positive ion mode using multiple reaction monitoring (MRM). Both methods were validated and the specificity, linearity, lower limit of quantitation (LLOQ), precision, accuracy, recoveries and stability were determined. The linear range for the low range assay was 0.01-5ng/mL for cocaine; in the high range assay values were 5-1000ng/mL for cocaine and 1-200ng/mL for EME. The correlation coefficient (R(2)) values for both assays were 0.993 or greater. The precision and accuracy for intra-day and inter-day were better than 13.0%. The recovery was above 85% and matrix effects were low with the matrix factor ranging from 0.817 to 1.10 for both analytes in both assays. The validated methods were successfully used to quantify the plasma concentrations of cocaine and EME in clinical pharmacokinetic and pharmacodynamic studies.

Population pharmacokinetics and prediction of dopamine D2 receptor occupancy after multiple doses of RBP-7000, a new sustained-release formulation of risperidone, in schizophrenia patients on stable oral risperidone treatment.

BACKGROUND AND OBJECTIVES: RBP-7000 is a long-acting formulation of risperidone administered once monthly via subcutaneous (SC) injections for the treatment of schizophrenia. The objectives of the present study were to characterize the pharmacokinetics of RBP-7000 after multiple doses in schizophrenic patients on stable oral risperidone therapy and to evaluate the switch between oral risperidone and SC injections of RBP-7000. METHODS: Data were collected in a phase IIa, open-label, multiple-ascending-dose study where 45 patients clinically stabilized on oral risperidone (2, 3 or 4 mg/day) were switched to receive 60, 90 or 120 mg/month SC injections of RBP-7000, respectively. Patients were thereafter switched back to oral risperidone. An integrated population pharmacokinetic model describing simultaneously risperidone and 9-hydroxyrisperidone after risperidone oral intake and RBP-7000 administration was developed in NON-MEM using 5,232 quantifiable plasma concentrations. Predictions of dopamine D2 receptor occupancy were derived using a previously published model. RESULTS: A two-compartment model with first-order absorption was selected for oral risperidone, while a three-compartment model with first-order absorption and a transit compartment absorption model was selected for RBP-7000. Body mass index was identified as a significant covariate affecting the initial absorption of risperidone following RBP-7000 injection. Steady state was reached after the second or third RBP-7000 injection but plasma concentrations close to steady-state values were obtained right after the first injection when switching from oral risperidone therapy. Predicted dopamine D2 receptor occupancy after repeated doses of 90 and 120 mg showed less fluctuation than after oral risperidone with acceptable ranges for clinical efficacy and a potentially safer profile with respect to extrapyramidal side effects. CONCLUSION: This analysis provided additional insight into the pharmacokinetics of RBP-7000 and for the comparison with oral risperidone treatment. The established model was used to support the design of a planned phase III study.

Concurrent validation of the Clinical Opiate Withdrawal Scale (COWS) and single-item indices against the Clinical Institute Narcotic Assessment (CINA) opioid withdrawal instrument.

INTRODUCTION: The Clinical Opiate Withdrawal Scale (COWS) is an 11-item clinician-administered scale assessing opioid withdrawal. Though commonly used in clinical practice, it has not been systematically validated. The present study validated the COWS in comparison to the validated Clinical Institute Narcotic Assessment (CINA) scale. METHOD: Opioid-dependent volunteers were enrolled in a residential trial and stabilized on morphine 30 mg given subcutaneously four times daily. Subjects then underwent double-blind, randomized challenges of intramuscularly administered placebo and naloxone (0.4 mg) on separate days, during which the COWS, CINA, and visual analog scale (VAS) assessments were concurrently obtained. Subjects completing both challenges were included (N=46). Correlations between mean peak COWS and CINA scores as well as self-report VAS questions were calculated. RESULTS: Mean peak COWS and CINA scores of 7.6 and 24.4, respectively, occurred on average 30 min post-injection of naloxone. Mean COWS and CINA scores 30 min after placebo injection were 1.3 and 18.9, respectively. The Pearson's correlation coefficient for peak COWS and CINA scores during the naloxone challenge session was 0.85 (p<0.001). Peak COWS scores also correlated well with peak VAS self-report scores of bad drug effect (r=0.57, p<0.001) and feeling sick (r=0.57, p<0.001), providing additional evidence of concurrent validity. Placebo was not associated with any significant elevation of COWS, CINA, or VAS scores, indicating discriminant validity. Cronbach's alpha for the COWS was 0.78, indicating good internal consistency (reliability). DISCUSSION: COWS, CINA, and certain VAS items are all valid measurement tools for acute opiate withdrawal.

Multi-center trial of baclofen for abstinence initiation in severe cocaine-dependent individuals.

BACKGROUND: Cocaine dependence is a major public health problem for which there is no FDA-approved pharmacological treatment. Baclofen is a GABA(B) receptor agonist that in preclinical and early pilot clinical trials has shown promise for the treatment of cocaine dependence. The purpose of this multi-site, double-blind study, was to compare the safety and efficacy of baclofen (60 mg/day) vs placebo in an 8-week treatment of individuals with severe cocaine dependence. The primary outcome measure was subjects' self-reported cocaine use substantiated by urine benzoylecgonine (BE). Analysis of the data did not show a significant difference between the groups treated with baclofen and placebo. The current results do not support a role for 60 mg baclofen in treating cocaine dependence in the population studied. The contrast of this result to earlier, preclinical and human pilot data with baclofen may reflect the trial's focus on severe cocaine-dependent users, and/or the need for a higher baclofen dose. Baclofen's potential as a relapse prevention agent was not tested by the current design, but may be a useful target for future studies.

Double-blind, placebo-controlled trial of selegiline transdermal system (STS) for the treatment of cocaine dependence.

BACKGROUND: Cocaine dependence is a major public health problem for which there is no FDA-approved pharmacological treatment. Selegiline is an irreversible selective inhibitor of monoamine oxidase type B (MAO-B) which may affect cocaine addiction through several potential mechanisms. In this study, selegiline transdermal system (STS) was compared to placebo as a treatment for cocaine dependence. This multi-site, double-blind trial of 300 subjects with cocaine dependence assessed the efficacy of selegiline using subject self-reported cocaine use substantiated by urine benzoylecgonine (BE) as the primary outcome measure. Analysis of the data did not show a significant effect for selegiline over placebo. This study does not support a role for selegiline in treating cocaine dependence. The contrast of this result to earlier, promising preclinical and human pilot data could be due to factors associated with sample size, patient characteristics, dose, or poor predictive validity of preclinical models.

Development of opioid formulations with limited diversion and abuse potential.

Non-medical abuse of prescription opioid medications is not a new phenomenon, but such use has been increasing in recent years. Various methods have been used and continue to be developed in an effort to limit diversion and abuse of opioid medications. A number of these methods will be described for opioid analgesic and addiction treatment formulations using relevant historical examples (e.g. propoxyphene, pentazocine, buprenorphine) as well as examples of formulations currently being considered or under development (e.g. oxycodone plus naltrexone, sustained-release buprenorphine). The focus, though not exclusively, will be on those formulations that represent a combination of an opioid agonist with an antagonist. These methods must take into consideration the pharmacokinetic profile of the agonist and antagonist, the expected primary route of abuse of the medication and the medication combination, the dose of medication that is likely to be abused, the availability of alternative drugs of abuse, and the population of potential abusers that is being targeted with the revised formulation.

Influence of psychotherapy attendance on buprenorphine treatment outcome.

We evaluated the influence of psychotherapy attendance on treatment outcome in 90 dually (cocaine and heroin) dependent outpatients who completed 70 days of a controlled clinical trial of sublingual buprenorphine (16 mg, 8 mg, or 2 mg daily, or 16 mg every other day) plus weekly individual standardized interpersonal cognitive psychotherapy. Treatment outcome was evaluated by quantitative urine benzoylecgonine (BZE) and morphine levels (log-transformed), performed three times per week. Repeated-measures linear regression was used to assess the effects of psychotherapy attendance (percent of visits kept), medication group, and study week on urine drug metabolite levels. Mean psychotherapy attendance was 71% of scheduled visits. Higher psychotherapy attendance was associated with lower urine BZE levels, and this association grew more pronounced as the study progressed (p=0.04). The inverse relationship between psychotherapy attendance and urine morphine levels varied by medication group, being most pronounced for subjects receiving 16 mg every other day (p=0.02). These results suggest that psychotherapy can improve the outcome of buprenorphine maintenance treatment for patients with dual (cocaine and opioid) dependence.

Buprenorphine: considerations for pain management.

New effective analgesics are needed for the treatment of pain. Buprenorphine, a partial mu-opioid agonist which has been in clinical use for over 25 years, has been found to be amenable to new formulation technology based on its physiochemical and pharmacological profile. Buprenorphine is marketed as parenteral, sublingual, and transdermal formulations. Unlike full mu-opioid agonists, at higher doses, buprenorphine's physiological and subjective effects, including euphoria, reach a plateau. This ceiling may limit the abuse potential and may result in a wider safety margin. Buprenorphine has been used for the treatment of acute and chronic pain, as a supplement to anesthesia, and for behavioral and psychiatric disorders including treatment for opioid addiction. Prolonged use of buprenorphine can result in physical dependence. However, withdrawal symptoms appear to be mild to moderate in intensity compared with those of full mu agonists. Overdoses have primarily involved buprenorphine taken in combination with other central nervous system depressants.

Decreasing international HIV transmission: the role of expanding access to opioid agonist therapies for injection drug users.

AIMS: To examine the role of expanded access to opioid agonist treatment as a means to decrease international HIV transmission. DESIGN: Review of the English language literature via Medline. MEASUREMENTS: Estimates of prevalence rates for injection drug use, HIV infection and treatment effect sizes for changes in opioid use, opioid injection, needle-sharing, injection-related HIV risk behavior and cost. FINDINGS: An estimated 12.6 million injection drug users internationally accounted for 10% of the 4.2 million new HIV infections in 2003. Ninety-three of the 136 countries (68%) that report injection drug use identify HIV infection related to this behavior. Observational studies of methadone treatment demonstrate decreases in opioid use, opioid injection, needle-sharing and lower rates of HIV prevalence and incidence. The effectiveness of buprenorphine in demonstrating similar findings is expected, although implementations and research are still emerging. The cost-effectiveness of opioid agonist treatment has been established. The barriers to international adoption of opioid agonist treatment, despite the research evidence and international guidelines, are discussed. CONCLUSIONS: Untreated opioid dependence leads to HIV transmission, on an international level. Opioid agonist treatments are associated with reductions in the frequency of opioid use, fewer injections and injection-related HIV risk behaviors and lower rates of HIV prevalence and incidence. Despite international recommendations, treatment for opioid-dependent injection drug users with methadone and buprenorphine is limited. Research, implementation efforts and political strategies to expand access to opioid agonist treatment are needed in order to combat the spread of HIV, especially in the developing world.

Pharmacists' and technicians' perceptions and attitudes toward dispensing buprenorphine/ naloxone to patients with opioid dependence.

OBJECTIVE: To assess the perceptions and attitudes of pharmacists and pharmacy technicians involved in an office-based opioid dependence treatment program using buprenorphine/naloxone. DESIGN: Cross-sectional attitudinal assessment. SETTING: Community, outpatient hospital, and clinic pharmacies. PARTICIPANTS: Pharmacists and technicians participating in a clinical trial of opioid dependence treatment using buprenorphine/naloxone. INTERVENTION: Written and telephone surveys followed by interviews with open-ended items. MAIN OUTCOME MEASURES: Attitudes and perceptions regarding opioid-dependent patients and use of buprenorphine/naloxone for treatment of opioid dependence. RESULTS: Pharmacies in seven states (New York, Virginia, Illinois, Florida, Texas, California, and Washington) participated in the clinical trial. A total of 40 pharmacists and pharmacy technicians responded to the initial written survey, representing 27 of the 32 pharmacies (84%). Follow-up interviews were obtained from one individual at 30 of those pharmacies (93.8%). Most pharmacy personnel (77.5%) involved with this study were not more concerned about theft or break-ins and would be willing to participate in opioid dependence treatment as the medication became available commercially (70%). The majority of respondents (85%) indicated that patients did not cause problems at their pharmacies. Compared with their experiences in administering other narcotic medications, most respondents did not express increased concern regarding prescription forgery (75%) or diversion (80%) of buprenorphine/naloxone. CONCLUSION: The majority of respondents expressed positive attitudes and perceptions regarding patients treated for opioid dependence with buprenorphine/naloxone.