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.

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.

Monthly Extended-Release Risperidone (RBP-7000) in the Treatment of Schizophrenia: Results From the Phase 3 Program.

PURPOSE/BACKGROUND: The Phase 3 program for RBP-7000, a once-monthly subcutaneous (SC) extended-release risperidone formulation approved for treatment of schizophrenia, consisted of a double-blind placebo-controlled trial (previously reported) and a 52-week open-label study of monthly RBP-7000 120 mg. The primary objective of the open-label study was to evaluate the long-term safety and tolerability of RBP-7000 in adults with schizophrenia. A secondary objective was to assess long-term maintenance of effectiveness. METHODS/PROCEDURES: The 52-week Phase 3 open-label study (NCT02203838) enrolled 92 rollover participants from the double-blind trial (NCT02109562) and 408 stable (Positive and Negative Syndrome Scale [PANSS] total score, ≤70) de novo participants. Participants received up to 13 monthly SC injections of RBP-7000 120 mg. Safety assessments included treatment-emergent adverse events, injection-site assessments, vital signs, laboratory and ECG parameters, extrapyramidal symptoms, and suicidality. Clinical outcomes included the PANSS and Clinical Global Impression-Severity. FINDINGS/RESULTS: Overall, 367 participants (73.4%) reported 1 or more treatment-emergent adverse event; the most common were injection-site pain (13.0%) and weight increase (12.8%). Most participants (>80%) experienced no injection-site reactions. No clinically meaningful changes were observed in laboratory or electrocardiogram values, vital signs, extrapyramidal symptoms, or suicidality. Over 12 months of exposure, mean PANSS scores continued to improve in rollover participants and remained stable among de novo participants. Mean Clinical Global Impression-Severity scores remained stable among all participants. IMPLICATIONS/CONCLUSIONS: Except for anticipated injection-site reactions, RBP-7000 demonstrated a favorable safety and tolerability profile similar to oral risperidone. Notably, PANSS scores continued to improve for participants from the pivotal study and remained stable for de novo participants.

Exposure-response analysis after subcutaneous administration of RBP-7000, a once-a-month long-acting Atrigel formulation of risperidone.

AIMS: A new, long-acting, subcutaneous (SC) formulation of risperidone (RBP-7000) has been developed for the treatment of schizophrenia to address issues of non-adherence associated with oral risperidone treatment. The objective of this work was to establish an exposure-response relationship between total active moiety (AM) plasma exposure (risperidone + 9-hydroxy-risperidone) and Positive and Negative Syndrome Scale (PANSS) or Clinical Global Impression severity (CGI-S) scores using data from a registration trial. METHODS: This was a Phase 3 randomized, double-blind, placebo-controlled, multicenter study in 354 patients to evaluate the efficacy, safety and tolerability of RBP-7000 (90 mg and 120 mg). Non-linear mixed effects modelling was used to develop an integrated population pharmacokinetic/pharmacodynamic (PK/PD) model that included a joint PK model for risperidone and 9-hydroxy-risperidone with placebo and drug-effect models to establish the relation between total AM exposure and PANSS or CGI-S scores. RESULTS: CYP2D6 poor and intermediate metabolizers had lower formation rates of 9-hydroxy-risperidone (94% and 76% lower, respectively) compared to the extensive CYP2D6 metabolizers. The maximum placebo-corrected relative decrease in PANSS score from baseline following RBP-7000 treatment was 5.4%, half of which could be achieved at plasma concentrations of 4.6 ng ml-1 of the total AM. A proportional odds model for the CGI-S score related the total AM plasma concentration to the probability of improving/worsening scores over time. CONCLUSIONS: Exposure-response analysis was established between total AM concentrations and PANSS and CGI-S scores, with good precision in parameter estimates. CYP2D6 phenotype on risperidone metabolism was the only identified covariate.

Quantitative determination of buprenorphine, naloxone and their metabolites in rat plasma using hydrophilic interaction liquid chromatography coupled with tandem mass spectrometry.

A rapid and sensitive LC-MS/MS method was developed and validated for the simultaneous determination of buprenorphine and its three metabolites (buprenorphine glucuronide, norbuprenorphine and norbuprenorphine glucuronide) as well as naloxone and its metabolite naloxone glucuronide in the rat plasma. A hydrophilic interaction chromatography column and a mobile phase containing acetonitrile and ammonium formate buffer (pH 3.5) were used for the chromatographic separation. Mass spectrometric detection was achieved by an electrospray ionization source in the positive mode coupled to a triple quadrupole mass analyzer. The calibration curves for the six analytes displayed good linearity over the concentration range 1.0 or 5.0-1000 ng/mL. The intra and inter-day precision (CV) ranged from 2.68 to 16.4% and from 9.02 to 14.5%, respectively. The intra- and inter-day accuracy (bias) ranged from -14.2 to 15.2% and from -9.00 to 4.80%, respectively. The extraction recoveries for all the analytes ranged from 55 to 86.9%. The LC-MS/MS method was successfully applied to a pharmacokinetic study of buprenorphine-naloxone combination in rats.

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.

Novel morpholine scaffolds as selective dopamine (DA) D3 receptor antagonists.

A new series of morpholine derivatives has been identified as selective DA D3 receptor antagonists; their in vitro profile and pharmacokinetic data are provided.

1,2,4-Triazolyl octahydropyrrolo[2,3-b]pyrroles: A new series of potent and selective dopamine D3 receptor antagonists.

A novel series of 1,2,4-triazolyl octahydropyrrolo[2,3-b]pyrroles showing high affinity and selectivity at the DA D3 receptor is reported here. Compounds endowed with high selectivity over the hERG channel were identified and their pharmacokinetic properties thoroughly analyzed. A few derivatives with appropriate developability characteristics were selected for further studies and progression along the screening cascade. In particular, derivative 60a, (DA D3 pKi=8.4, DA D2 pKi=6.0 and hERG fpKi=5.2) showed a balanced profile and further refinements are in progress around this molecule.

The selective dopamine D3 receptor antagonist SB-277011A attenuates drug- or food-deprivation reactivation of expression of conditioned place preference for cocaine in male Sprague-Dawley rats.

We determined the effect of the selective dopamine D3 receptor antagonist SB-277011A on reactivation of conditioned place preference (CPP) to cocaine elicited by priming injections of cocaine or exposure to food deprivation stress (21 h) in male Sprague-Dawley rats. Animals paired with the cocaine-associated chamber displayed a robust and consistent CPP response. This CPP was extinguished after repeated pairings of the conditioned stimuli (cocaine-paired chamber contextual cues) in the absence of the unconditioned stimulus (cocaine). Twenty-four hours later, the administration of 5 mg kg(-1) i.p. of cocaine (immediately before the test) or exposure to 21 h of food deprivation reactivated the expression of the cocaine-induced CPP. In contrast, administration of 1 ml kg(-1) i.p. of vehicle did not reactivate the CPP response. Administration of the selective dopamine D3 receptor antagonist SB-277011A (3-24 mg kg(-1) i.p.) 30 min before cocaine administration on the test day produced a significant attenuation of CPP reactivation. Reactivation of the CPP response produced by food deprivation was also significantly attenuated by SB-277011A (6 or 12 mg kg(-1) i.p.) given 30 min before the test session. SB-277011A (12 or 24 mg kg(-1) i.p.) did not itself produce reactivation of the CPP response. Overall, these results suggest that the reactivation of the incentive value of drug-associated cues by cocaine or food deprivation is attenuated by selective antagonism of D3 receptors.

The selective D3 receptor antagonist SB-277011A attenuates morphine-triggered reactivation of expression of cocaine-induced conditioned place preference.

We examined the effect of acute administration of the selective D3 receptor antagonist SB-277011A on morphine-triggered reactivation of cocaine-induced conditioned place preference (CPP) in adult male Sprague-Dawley rats. Repeated pairing of animals with 15 mg/kg i.p. of cocaine HCl or vehicle to cue-specific CPP chambers produced a significant CPP response compared to animals paired only with vehicle in both chambers. Expression of the CPP response to cocaine was then extinguished by repeatedly giving the animals vehicle injections in the cocaine-paired chambers. The magnitude of the CPP response after extinction was not significantly different from that of animals paired only with vehicle. Expression of the extinguished CPP response was reactivated by acute administration of 5 mg/kg i.p. of morphine but not by vehicle. Acute administration of 6 or 12 mg/kg i.p. (but not 3 mg/kg) of SB-277011A significantly attenuated morphine-triggered reactivation of the cocaine-induced CPP. SB-277011A itself (12 mg/kg i.p.) did not reactivate the extinguished CPP response. Overall, SB-277011A decreases the incentive motivational actions of morphine. The present findings suggest that central D3 dopamine receptors are involved in relapse to cocaine-seeking behavior, that a final common neural mechanism exists to mediate the incentive motivational effects of psychostimulants and opiates, and that selective dopamine D3 receptor antagonists constitute promising compounds for treating addiction.

Current Perspectives on Selective Dopamine D3 Receptor Antagonists/Partial Agonists as Pharmacotherapeutics for Opioid and Psychostimulant Use Disorders.

Over three decades of evidence indicate that dopamine (DA) D3 receptors (D3R) are involved in the control of drug-seeking behavior and may play an important role in the pathophysiology of substance use disorders (SUD). The expectation that a selective D3R antagonist/partial agonist would be efficacious for the treatment of SUD is based on the following key observations. First, D3R are distributed in strategic areas belonging to the mesolimbic DA system such as the ventral striatum, midbrain, and ventral pallidum, which have been associated with behaviors controlled by the presentation of drug-associated cues. Second, repeated exposure to drugs of abuse produces neuroadaptations in the D3R system. Third, the synthesis and characterization of highly potent and selective D3R antagonists/partial agonists have further strengthened the role of the D3R in SUD. Based on extensive preclinical and preliminary clinical evidence, the D3R shows promise as a target for the development of pharmacotherapies for SUD as reflected by their potential to (1) regulate the motivation to self-administer drugs and (2) disrupt the responsiveness to drug-associated stimuli that play a key role in reinstatement of drug-seeking behavior triggered by re-exposure to the drug itself, drug-associated environmental cues, or stress. The availability of PET ligands to assess clinically relevant receptor occupancy by selective D3R antagonists/partial agonists, the definition of reliable dosing, and the prospect of using human laboratory models may further guide the design of clinical proof of concept studies. Pivotal clinical trials for more rapid progression of this target toward regulatory approval are urgently required. Finally, the discovery that highly selective D3R antagonists, such as R-VK4-116 and R-VK4-40, do not adversely affect peripheral biometrics or cardiovascular effects alone or in the presence of oxycodone or cocaine suggests that this class of drugs has great potential in safely treating psychostimulant and/or opioid use disorders.

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.

The acute administration of the selective dopamine D(3) receptor antagonist SB-277011A reverses conditioned place aversion produced by naloxone precipitated withdrawal from acute morphine administration in rats.

We examined the effect of SB-277011A, a selective D(3) receptor antagonist, on the conditioned place aversion (CPA) response associated with naloxone-induced withdrawal from acute morphine administration in male Sprague-Dawley rats. Morphine (5.6 mg/kg i.p.) was given, followed 4 hrs later by naloxone (0.3 mg/kg i.p.) and prior to placing the animals in one specific chamber of the test apparatus. All animals were subjected to 2 of these trials. A significant CPA occurred in animals that received an i.p. injection of vehicle 30 minutes prior to the measurement of chamber preference. The pretreatment of animals (30 minutes prior to testing) with 3 mg/kg i.p. of SB-277011A did not significantly alter the CPA compared to animals treated with vehicle (1 ml/kg i.p. of deionized distilled water). In contrast, the acute pretreatment of animals with 6, 12 or 24 mg/kg i.p. of SB-277011A significantly decreased the CPA compared to vehicle-treated animals. In fact, the 12 and 24 mg/kg doses of SB-277011A significantly increased the time spent in the chamber where animals were paired with morphine and naloxone. These results suggest that the selective antagonism of D(3) receptors attenuates the CPA produced by a model of naloxone-induced withdrawal from acute morphine dependence.

The introduction of a novel formulation of buprenorphine into organized health systems.

Background: Effective medications for opioid use disorder (MOUD) are underutilized. This exploratory study used real-world data to analyze US distribution patterns of buprenorphine extended-release (BUP-XR) within organized health systems (OHS), including the Veterans Health Administration (VHA), Indian Health Service (IHS), criminal justice system (CJS), and integrated delivery networks (IDNs). Methods: National BUP-XR distribution data within each OHS were available from WNS Global Services and were evaluated from July 2019 through July 2020. BUP-XR distribution data by OHS subtype (VHA, IHS, CJS, IDN) and state were aggregated and reported. Results: The total distribution of BUP-XR increased from 6,721 units in the second half of 2019 (H2'19) to 12,925 in the first half of 2020 (H1'20). OHS distribution increased from H2'19 to H1'20 in every subtype but was primarily driven by IDN distribution growth. IDNs accounted for 73% of total units in H2'19 and continued to grow in H1'20. In H1'20, IDNs accounted for 78%, VHA for 12%, CJS for 6%, and IHS for 4%. IDN distribution for BUP-XR increased from 4,911 to 10,100 units, showing the highest growth rate of 106% within all OHS subtypes. The states with the highest total BUP-XR distribution over the 12-month period were Massachusetts (4,534), Pennsylvania (3,773), and California (1,866). Conclusions: Overall distribution of BUP-XR, as a treatment option for OUD, is increasing; however, access to MOUD varies greatly across OHS subtypes and geography. Identifying and overcoming barriers to appropriate MOUD use is critical in addressing the opioid crisis.

Buprenorphine exposure levels to optimize treatment outcomes in opioid use disorder.

The severity of the ongoing opioid crisis, recently exacerbated by the COVID-19 pandemic, emphasizes the importance for individuals suffering from opioid use disorder (OUD) to have access to and receive efficacious, evidence-based treatments. Optimal treatment of OUD should aim at blocking the effects of illicit opioids while controlling opioid craving and withdrawal to facilitate abstinence from opioid use and promote recovery. The present work analyses the relationship between buprenorphine plasma exposure and clinical efficacy in participants with moderate to severe OUD using data from two clinical studies (39 and 504 participants). Leveraging data from placebo-controlled measures assessing opioid blockade, craving, withdrawal and abstinence, we found that buprenorphine plasma concentrations sustained at 2-3 ng/ml (corresponding to ≥70% brain mu-opioid receptor occupancy) optimized treatment outcomes in the majority of participants, while some individuals (e.g., injecting opioid users) needed higher concentrations. Our work also included non-linear mixed effects modeling and survival analysis, which identified a number of demographic, genetic and social factors modulating treatment response and retention. Altogether, these findings provide key information on buprenorphine plasma levels that optimize clinical outcomes and increase the likelihood of individual treatment success. NLM identifiers: NCT02044094, NCT02357901.

Orexin-1 receptor antagonist SB-334867 reduces the acquisition and expression of cocaine-conditioned reinforcement and the expression of amphetamine-conditioned reward.

Preclinical evidence suggests an important role of the brain orexin system in behaviours related to drug addiction. This study aimed at assessing the effect of the orexin-1 receptor antagonist SB-334867 on aspects of psychostimulant-conditioned behaviours that are thought to contribute to the maintenance of and relapse to psychostimulant drug use. Rats were first allowed to nose poke for cocaine infusions associated with a cue light presentation (conditioned stimulus; CS) over five daily sessions. Subsequently, drug-free rats were tested for the acquisition of a new response in which presses on a novel active lever led to the presentation of the previously paired CS. We tested SB-334867 in two conditions, SB-334867 was given either before each cocaine self-administration or before the initial four sessions of acquisition for a novel instrumental responding paired with the CS (conditioned reinforcement). The effect of SB-334867 was also tested on the expression of conditioned place preference to d-amphetamine. The rats treated with SB-334867 before each cocaine self-administration session subsequently showed reduced active lever pressing compared with controls in the initial days of the conditioned reinforcement. In the second study, untreated rats showed normal acquisition of discriminated responding preferential for the lever providing the cocaine cue. In contrast, SB-334867 decreased the number of active lever pressing (compared with the control) with significant effects in all sessions. Finally, SB-334867 blocked the expression of d-amphetamine-induced conditioned place preference. These results suggest that orexin-1 receptor antagonism could offer therapeutic potential in reducing the impact of psychostimulant-predictive stimuli that contribute to compulsive drug seeking in human drug users.

The GABA-B positive modulator GS39783 decreases psychostimulant conditioned-reinforcement and conditioned-reward.

Baclofen, a γ-amino-butyric-acid (GABA)(B) receptor agonist, can reduce cue-enhanced cocaine-seeking in rats and attenuate cue-evoked craving in cocaine addicts. However, baclofen also has sedative effects that might interfere with its efficacy in reducing cocaine's rewarding effects. The present study aimed at comparing the effects of baclofen with the GABA(B) -receptor positive allosteric modulator GS39783 on psychostimulant conditioned cues. Two identically trained groups of male Lister-Hooded rats were baselined on a new responding for a light stimulus previously paired with cocaine self-administration. One group was treated with the GABA(B) -receptor positive allosteric modulator GS39783 (0, 10, 30, 100 mg/kg, i.p.), the other with baclofen (0, 0.6, 1.25, 1.9, 2.5 mg/kg, i.p.). In another series of experiments, male Wistar rats received GS39783 (0, 10, 30, 100 mg/kg, i.p.) or baclofen (1.25 mg/kg) prior to the expression of a conditioned place preference (CPP) to amphetamine (2 mg/kg i.p.). Both GS39783 (30 and 100 mg/kg) and baclofen (2.5 mg/kg) significantly decreased responding for the cocaine cue; however, only GS39783 (30 mg/kg) reduced lever pressing responding without interfering with locomotor activity. Both GS39783 (30 and 100 mg/kg) and baclofen (1.25 mg/kg), significantly blocked the expression of amphetamine CPP without affecting locomotor activity. These findings suggest that GABA(B) positive allosteric modulators can modulate discrete and contextual psychostimulant conditioned stimuli in a manner dissociable from unwanted sedative effects and may offer a novel therapeutic approach to treat cravings and relapse to drug-taking triggered by stimuli associated with psychostimulant use.

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.