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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

A model-based approach to characterize the population pharmacokinetics and the relationship between the pharmacokinetic and safety profiles of RBP-7000, a new, long-acting, sustained-released formulation of risperidone.

RBP-7000 is a sustained-release (once-monthly injection for subcutaneous administration) formulation of risperidone using the ATRIGEL® Delivery System, developed for treatment of schizophrenia to address compliance issues associated with oral administration. The objective of this analysis was to report the results of a population pharmacokinetic analysis and to describe the relationship between risperidone and 9-hydroxyrisperidone levels with dopamine (DA) D2-receptor occupancy, prolactin levels, and adverse events using data collected in 45 clinically stable schizophrenic patients receiving RBP-7000 in single ascending doses (risperidone) of 60, 90, and 120 mg. The population PK model accounted for an initial peak, a delayed and slow delivery, the disposition of risperidone, and the conversion of risperidone to 9-hydroxyrisperidone.

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.

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

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.

Extended vs short-term buprenorphine-naloxone for treatment of opioid-addicted youth: a randomized trial.

Context: The usual treatment for opioid-addicted youth is detoxification and counseling. Extended medication-assisted therapy may be more helpful.

Objective: To evaluate the efficacy of continuing buprenorphine-naloxone for 12 weeks vs detoxification for opioid-addicted youth.

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

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.

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.

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.

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.

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.

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.

Recent advances in the treatment of opiate addiction.

Although addiction to heroin and other opiates is a major public health issue in the United States and many other countries, advances in pharmacologic and nonpharmacologic treatment have been made. Some of these advances represent a major shift from traditional treatment philosophies, whereas others are characterized by more subtle, though important, improvements. This review discusses recent advances in opiate-addiction treatment in the context of three main domains: the use of buprenorphine and buprenorphine/naloxone in an office-based paradigm, psychosocial treatment and the addressing of medical and psychiatric comorbidity, and harm reduction strategies.

Randomized trial of buprenorphine for treatment of concurrent opiate and cocaine dependence.

Background: Buprenorphine is a partial mu-opiate agonist and kappa-opiate antagonist with established efficacy in the treatment of opiate dependence. Its efficacy for cocaine dependence is uncertain. This study evaluated buprenorphine for the treatment of concomitant cocaine and opiate dependence.

Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone.

Background: Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone has been proposed, but its efficacy and safety have not been well studied.

Methods: We conducted a multicenter, randomized, placebo-controlled trial involving 326 opiate-addicted persons who were assigned to office-based treatment with sublingual tablets consisting of buprenorphine (16 mg) in combination with naloxone (4 mg), buprenorphine alone (16 mg), or placebo given daily for four weeks. The primary outcome measures were the percentage of urine samples negative for opiates and the subjects' self-reported craving for opiates.