Buprenorphine Research Articles

Sexual Functioning and Opioid Maintenance Treatment in Women. Results From a Large Multicentre Study

Opioid maintenance treatment (OMT) is the most widespread therapy for both females and males opioid addicts. While many studies have evaluated the OMT impact on men’s sexuality, the data collected about the change in women’s sexual functioning is still limited despite the fact that it is now well-known that opioids - both endogenous and exogenous - affect the endocrine system and play an important role in sexual functioning. The present study aims to determine how OMT with buprenorphine (BUP) or methadone (MTD) affects sexual health in women; examining also any possible emerging correlation between sexual dysfunction (SD), type of opioid and patients’ mental health. This multi-center study case recruited 258 female volunteers attending Italian public Addiction Outpatients Centers that were stabilized with OMT for at least 3 months. SD was assessed with the Arizona Sexual Experience Scale. The twelve-item General Health Questionnaire was used to assess participants’ mental health conditions. The results show that 56.6% of women receiving OMT for at least 3 months presented SD without significant differences between MTD e BUP groups. The majority of the subjects with SD have a poorer quality of intimate relationships and worse mental health than the average. To the best of our knowledge, the present study is the largest report on the presence of SDs in women as a side effects of MTD and BUP used in OMT. Since SDs cause difficulties in intimate relationships, lower patients’ quality of life and interfere with OMT beneficial outcomes, we recommend that women undertaking an opioid therapy have routine screening for SD and we highlight the importance to better examine opioid-endocrine interactions in future studies in order to provide alternative potential treatments such as the choice of opioid, opioid dose reduction and hormone supplementation.

Simultaneous Transdermal Delivery of Buprenorphine Hydrochloride and Naltrexone Hydrochloride by Iontophoresis.

The opioids buprenorphine hydrochloride (BUP) and naltrexone hydrochloride (NTX) show promise as a combination treatment for addiction, but no means of delivering the two compounds in one medicine currently exist. In this paper, we report sufficient input rates of both these drugs from one iontophoretic transdermal drug delivery system. Experiments were performed using dermatomed pig skin mounted in glass side-bi-side cells. BUP and NTX were iontophoretically delivered together from the anode using direct constant current from Ag/AgCl electrodes. The transdermal drug fluxes and the masses of drugs in both the stratum corneum and the underlying epidermis/dermis were measured. The apparent electroosmotic flow was quantified using a neutral marker (acetaminophen). The effects of donor composition (drug concentration/molar fraction and pH), current density and profile, and the choice of receptor solution were assessed. Iontophoresis dramatically increased the flux of both drugs compared to passive control values. Target fluxes (calculated from literature clearance values and required therapeutic plasma concentrations) were greatly exceeded for NTX and were met for BUP. The latter accumulated in the skin and suppressed electroosmotic flow, inhibiting both its own flux and that of NTX. NTX, in turn, negatively influenced the flux of BUP via co-ion competition. Lowering current density by increasing the delivery area resulted in increased electroosmotic flow but did not significantly affect current-normalized drug fluxes. Delivering the drugs from both electrodes and reversing the polarity for every 2 h did not increase the flux of either compound. In summary, during iontophoresis, BUP and NTX inhibited each other's flux by two distinct mechanisms. While the more complex behavior of BUP complicates the optimization of this drug combination, iontophoresis nevertheless appears to be a feasible approach for the controlled codelivery of NTX and BUP through the skin.

Concomitant Heroin and Cocaine Use among Opioid-Dependent Patients during Methadone, Buprenorphine or Morphine Opioid Agonist Therapy

Background: Among all the treatment methods developed so far, opioid agonist treatment (OAT) is the most effective therapy for opioid dependence. While methadone (MTD) is the most commonly used, fewer data are available on alternative opioid agonist. The aim of this study was to assess the efficacy of buprenorphine (BUP) and slow-released morphine compared to MTD with regard to the reduction of concomitant heroin and cocaine use. Methods: This cross-sectional study included 105 patients receiving MTD, BUP, or slow-release morphine as opioid agonist therapy at the Psychiatric Hospital of Zurich. Illicit drug use was assessed using a retrospective 3-month hair toxicology analysis to quantify concentrations of heroin degradation products and metabolites, as well as cocaine and cocaine metabolites. We have also collected self-reports, but in the data of the study, only the results of the hair analysis were considered. Results: BUP-treated patients showed lower rates of illicit opiate consumption in comparison to the group treated with MTD or slow-released morphine (p < 0.05). The proportion of heroin-positive hair samples associated with slow-release morphine treatment was similar to the proportion associated with MTD treatment. Neither the MTD vs. slow-released morphine groups nor the BUP vs. MTD groups showed significant differences in the number of patients consuming cocaine although patients in the BUP group had significantly lower concentrations of cocaine in hair testing compared to the patients in the MTD group. Prevalence of cocaine consumption was also significantly lower in the BUP group compared to patients in the slow-release morphine group (p < 0.05). Conclusion: This study suggests that BUP OAT is associated with reduced additional opiate co-use.

Ascorbic Acid Improves the Stability of Buprenorphine in Frozen Whole Blood Samples.

Buprenorphine (BUP) was not long-term stable in whole blood samples preserved with fluoride citrate (FC) and fluoride oxalate (FX) mixtures when stored at -20°C. On average, only half of the initial concentrations of BUP was recovered after 12 weeks of storage at -20°C when interrupted by 3-4 thaw/freeze cycles. Norbuprenorphine (NBUP) was less unstable; approximately 90% was recovered after 12 weeks of storage at -20°C. The instability was less at 5°C, but the formation of BUP and NBUP from their glucuronides was observed at that temperature, especially in FC-preserved blood. The substances were stable for at least 5 months when stored uninterrupted at -80°C. The instability of BUP and NBUP in FC- and FX-preserved whole blood stored at -20°C was eliminated when the samples were modified with 30 mM ascorbic acid (ASC) prior to storage. The mean recoveries were greater than 95% after a 5-month interrupted storage period at -20°C when modified with ASC.

P138: Management of opioid withdrawal: A qualitative examination of current practices and barriers to prescribing buprenorphine in a Canadian emergency department

Introduction: The opioid crisis persists, and in the context of this urgency and new practice guidelines, the practice of buprenorphine (BUP) prescription is expanding across Canadian emergency departments (EDs). The objective of this study was to identify current knowledge, attitudes and behaviours to managing opioid use disorder (OUD) in the ED, including barriers and facilitators to prescribing BUP. Methods: Forty ED staff physicians were randomly invited to participate from an urban Toronto ED which recently received continuing medical education in addictions, and whose hospital established an addictions follow-up clinic. Individual semi-structured interviews with the 19 physicians who self-selected to participate were grounded in phenomenology, allowing for in-depth accounts of participants’ lived experience and viewpoints on their role in addressing OUD. Thematic analysis was achieved through multiple readings; themes were coded using Dedoose software by two researchers. Themes were further organized as facilitators, barriers, and proposed solutions. Results: Opioid withdrawal management in the ED varied significantly between these practitioners in the same practice group. Facilitators to treating withdrawal and initiating BUP in the ED were rooted in three contributors to physician empowerment: knowledge about OUD and BUP, positive patient and provider experience with substitution therapy in the past, and exposure to physician champions to guide their practice. Systems-level facilitators included timely access to follow-up care and an available order set. Barriers included provider inexperience: missing subtle presentations of withdrawal, lacking feedback on treatment effectiveness, and reported uncertainty about the protocol from nursing staff. The ED environment also limits time to counsel effectively and discourages taking up a bed both to wait for withdrawal onset and for BUP induction. Other barriers were concerns about precipitating withdrawal, prescribing a chronic medication in acute care, and patient attitudes. Conclusion: This is the first study describing barriers and facilitators to addressing OUD and prescribing BUP in the ED. These findings suggest a role for home induction, involvement of allied health professionals in BUP counseling, and heightened continuing medical education. Results will inform departmental efforts across Canada to implement BUP prescribing as standard of care for patients in opioid withdrawal.

PMD5 ASSOCIATION BETWEEN BUPRENORPHINE RETENTION/ADHERENCE AND HEALTHCARE RESOURCE UTILIZATION AND ASSOCIATED COSTS: A LITERATURE REVIEW

Buprenorphine (BUP) is commonly used in medication-assisted treatment for opioid use disorder (OUD). This study examined the association between BUP retention and healthcare resource utilization and associated costs (HCRU). A literature review was performed to examine the impact of BUP treatment retention on HCRU among patients with OUD. The PubMed database was searched (2000 – present) with keywords including “buprenorphine”, “OUD”, ”dependence”, “retention”, “adherence”, “healthcare utilization”, and “costs”. Exclusion criteria include retention/adherence as the study outcome, HCRU not as an outcome, and special populations (adolescents or prisoners). Out of a total of 234 studies, six studies were included. The Schwarz 2012 study reported data from a retrospective chart review conducted at local community centers (n=209) while the other five studies [(Manhapra 2017: veteran health administration records (n=3,151); Manhapra 2018 (n=16,190) and Ronquest 2018 (n=21,773): MarketScan claims; Tkacz 2013 (n=455) and Ruetsch 2017 (n=477): Aetna data]. Higher retention rates were found to be associated with reduced emergency department visits across all studies. Manhapra 2017 also found significant association between retention and reduction in mental health inpatient treatment, outpatient visits, and substance abuse visits. In the Tkacz study, patients adherent to BUP (medication possession ratio>=0.8) incurred $10,982 (±$4,142) for hospitalization during 12-month follow-up period, compared to $26,470 (±$3,163) for those not adherent (P<0.001). Similar correlation between higher adherence and lower healthcare utilization was also noted in the Reutsch study. However, no significant difference in hospitalization and associated costs was observed among patients demonstrating retention versus those who did not (Schwarz and Ronquest studies). This literature review showed a correlation between higher retention/adherence to BUP treatment and lower HCRU in patients with OUD. Further studies are warranted to explore cost-effectiveness of BUP retention and HCRU among patients with OUD in the real-world setting.

User-centred clinical decision support to implement emergency department-initiated buprenorphine for opioid use disorder: protocol for the pragmatic group randomised EMBED trial

IntroductionThe goal of this trial is to determine whether implementation of a user-centred clinical decision support (CDS) system can increase adoption of initiation of buprenorphine (BUP) into the routine emergency...

A Monthly Buprenorphine Injectable: Another Option for Treating Opioid Use Disorder

Although monthly, injectable, long-acting naltrexone, oral buprenorphine, and methadone are effective treatments for opioid use disorder (OUD), they

Suboxone Treatment and Recovery Trial (STAR-T): Study Protocol for a Randomised Controlled Trial of Opioid Medication Assisted Treatment with Adjunctive Medication Management Using Therapeutic Drug Monitoring and Contingency Management.

Introduction Opioid assisted treatment (OAT) with buprenorphine (BUP) is front-line medical maintenance intervention for illicit and prescription opioid use disorder (OUD). In many clinics, opioid medication is dispensed for several days for self-administration. This provides flexibility to the patient but may compromise the effectiveness of OAT because of nonadherence or medication diversion. OAT can be delivered as an entirely supervised intervention, but many patients discontinue treatment under this arrangement and dispensing costs may be prohibitive. An alternative is to enable patients to receive take-home doses contingent on OAT adherence guided by a medication management framework using Therapeutic Drug Monitoring (TDM) alongside negative urine drug screens (UDS) to provide evidence of abstinence. TDM is recommended to monitor adherence with BUP but it has not been applied in OAT programs and evaluation research to date. Methods The Suboxone Treatment and Recovery Trial (STAR-T) is a single site, 16-week, parallel-group, randomised controlled trial. The aim of the study is to determine the effectiveness of a medication management framework including TDM and UDS to enable patients enrolled on outpatient OAT (with buprenorphine/naloxone [sublingual film formulation; BUP/NX-F; Suboxone™]) to receive stepped take-home doses. Following stabilisation during inpatient care, adult participants with illicit or prescription OUD were allocated (1:1) to receive (1) BUP/NX-F plus medication management for take-home doses based on TDM, UDS, and contingency management protocol (the experimental group) or (2) BUP/NX-F plus UDS only (treatment-as-usual, the control group). The primary outcome is the mean percentage of negative UDS over 16 weeks. The secondary outcome is treatment retention defined as completion of 16 weeks of OAT without interruption. There will be an exploratory analysis of the association between participant characteristics, clinical data, and outcomes. Conclusions Providing BUP/NX-F take-home doses contingent on adherence and opioid abstinence may enable OAT to be delivered flexibly and effectively. Trial Registration ISRCTN41645723 is retrospectively registered on 15/11/2015.

To Compare and Assess Quality of Analgesia and Side Effects following the use of Fentanyl, Buprenorphine Hydrochloride, Bupivacaine Hydrochloride, through the Thoracic Epidural Catheter

To Compare and Assess Quality of Analgesia and Side Effects following the use of Fentanyl, Buprenorphine Hydrochloride, Bupivacaine Hydrochloride, through the Thoracic Epidural Catheter

Computerized Clinical Decision Support System for Emergency Department-Initiated Buprenorphine for Opioid Use Disorder: User-Centered Design.

BackgroundEmergency departments (EDs) frequently care for individuals with opioid use disorder (OUD). Buprenorphine (BUP) is an effective treatment option for patients with OUD that can safely be initiated in the ED. At present, BUP is rarely initiated as a part of routine ED care. Clinical decision support (CDS) could accelerate adoption of ED-initiated BUP into routine emergency care.ObjectiveThis study aimed to design and formatively evaluate a user-centered decision support tool for ED initiation of BUP for patients with OUD.MethodsUser-centered design with iterative prototype development was used. Initial observations and interviews identified workflows and information needs. The design team and key stakeholders reviewed prototype designs to ensure accuracy. A total of 5 prototypes were evaluated and iteratively refined based on input from 26 attending and resident physicians.ResultsEarly feedback identified concerns with the initial CDS design: an alert with several screens. The timing of the alert led to quick dismissal without using the tool. User feedback on subsequent iterations informed the development of a flexible tool to support clinicians with varied levels of experience with the intervention by providing both one-click options for direct activation of care pathways and user-activated support for critical decision points. The final design resolved challenging navigation issues through targeted placement, color, and design of the decision support modules and care pathways. In final testing, users expressed that the tool could be easily learned without training and was reasonable for use during routine emergency care.ConclusionsA user-centered design process helped designers to better understand users’ needs for a Web-based clinical decision tool to support ED initiation of BUP for OUD. The process identified varying needs across user experience and familiarity with the protocol, leading to a flexible design supporting both direct care pathways and user-initiated decision support.

Comparing the Antinociceptive Effects of Methamphetamine, Buprenorphine, or Both After Chronic Treatment and Withdrawal in Male Rats

Introduction:Methamphetamine (Meth) and Buprenorphine (BUP) modulate pain perception. However, the antinociceptive effects of their interactions, which affect through different systems, are unclear in rats. This study aimed to compare the analgesic effects of Meth, BUP, and their coadministration, as well as the effect of withdrawal from these substances on nociception in male rats.Methods:In this experiment, 40 male Wistar rats (weight: 250–300 g) were categorized into four groups: control, Meth, BUP, or BUP+Meth. After seven days of treatments, the antinociceptive effects were assessed using the hot plate and the tail flick tests. The differences among the groups were analyzed with ANOVA and Tukey’s post hoc tests. P values less than 0.05 were considered significant.Results:Meth and BUP increased the reaction times during the hot plate and tail flick tests. The combination of Meth and BUP increased reaction time more than Meth or BUP alone.Conclusion:The significantly high reaction times in rats treated with Meth and BUP indicate that these substances have antinociceptive effects. In addition, Meth enhanced the antinociceptive effects of BUP. These synergistic effects might occur through the dopaminergic, serotonergic, and or adrenergic systems.

Long-lasting buprenorphine implant recommended by EMA committee

Long-lasting buprenorphine implant recommended by EMA committee

Feasibility and efficacy of sublingual buprenorphine tablets in managing acute postoperative pain after elective breast cancer surgeries: A series of 10 cases.

Poorly controlled perioperative surgical pain is a consistent risk factor for developing post mastectomy pain syndrome (PMPS).[1] The incidence of chronic pain after mastectomy is as high as 25-60%, which is a range derived from several studies.[2] American Society of Anesthesiologists (ASA) recommends a multimodal approach to postoperative pain management whenever possible which includes use of non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, alpha-2 agonists, N-methyl D-aspartate receptor antagonists, gabapentinoids, dexamethasone, anti-depressants and peripheral nerve blocks.[3] Buprenorphine hydrochloride is a partial μ-receptor agonist, OLR-1 (Oxidized Low-density lipoprotein Receptor) agonist, delta and kappa receptor antagonist approved for managing acute surgical pain, cancer pain and non-cancer pain.[4] Sublingual (SL) buprenorphine is available in the form of 200 μg tablets which has been used with good results for managing acute postoperative pain.[5] In the present case series, we have investigated the feasibility and efficacy of SL buprenorphine in managing acute postoperative pain after mastectomy.

Intravenous Misuse of Methadone, Buprenorphine and Buprenorphine-Naloxone in Patients Under Opioid Maintenance Treatment: A Cross-Sectional Multicentre Study

Background: The act of intravenous misuse is common in patients under opioid maintenance treatment (OMT), but information on associated factors is still limited. Objectives: To explore factors associated with (a) intravenous OMT misuse, (b) repeated misuse, (c) emergency room (ER) admission, (d) misuse of different OMT types and (e) concurrent benzodiazepine misuse. Methods: We recruited 3,620 patients in 27 addiction units in Italy and collected data on the self-reported rate of intravenous injection of methadone (MET), buprenorphine (BUP), BUP-naloxone (NLX), OMT dosage and type, experience of and reason for misuse, concurrent intravenous benzodiazepine misuse, pattern of ­misuse in relation to admission to the addiction unit and ER ­admissions because of misuse. According to inclusion/exclusion criteria, 2,585 patients were included. Results: Intravenous misuse of OMT substances was found in 28% of patients with no difference between OMT types and was associated with gender, age, type of previous opioid abuse and intravenous benzodiazepine misuse. Repeated OMT misuse was reported by 20% (i.e., 71% of misusers) of patients and was associated with positive OMT misuse experience and intravenous benzodiazepine misuse. Admission to the ER because of misuse complications was reported by 34% of patients, this outcome being associated with gender, employment, type of previous opioid abuse and intravenous benzodiazepine misuse. OMT dosage was lower than the recommended maintenance dosage. Conclusions: We offered new information on factors associated with intravenous OMT misuse, repeated misuse and ER admission in Italian patients under OMT. Our data indicate that BUP-NLX misuse is not different from that of BUP or MET. Choosing the more expensive BUP-NLX over MET will likely not lead to the expected reduction of the risk of injection misuse of the OMT. Instead of prescribing new and expensive OMT formulations, addiction unit physicians and medical personnel should better focus on patient’s features that are associated with a higher likelihood of misuse. Care should be paid to concurrent benzodiazepine and OMT misuse.

649: Impact of hepatitis C virus infection on buprenorphine dose in pregnancy

Buprenorphine (BUP) is the preferred medication for opioid maintenance therapy in pregnancy and is primarily metabolized in the liver. Given that hepatitis C virus (HCV) infection is common in opiate dependent individuals, we sought to determine whether liver dysfunction related to HCV infection impacts the dose of BUP needed during pregnancy. A retrospective cohort study of 266 pregnancies with antenatal exposure to BUP from 2015-2018 at a single center. Individuals positive for HCV infection versus women negative for HCV infection were compared. For HCV prevalence, Kruskal-Wallis tests were performed with continuous variable and Chi-Square tests with categorical variables. Spearman correlation tests were used to assess the relationship between BUP dose and HCV status. In patients with antenatal exposure to BUP, the average age was 29 (18-42) years and 99% were Caucasian. HCV infection was present in 39% of the population. Patients with HCV infection required less dose increases throughout pregnancy (p=0.02). Among the HCV positive cohort, a positive correlation was seen between HCV viral load and the liver enzymes AST (0.30, p=0.003) and ALT (0.25, p=0.01). A negative correlation was noted among the HCV positive cohort for HCV viral load in relation to BUP dose during the second trimester (-0.27, p=0.01) and third trimester (-0.20, p=0.04). HCV infection was associated with less of an increase in BUP dose throughout pregnancy compared to mothers without HCV infection. Among HCV positive mothers, a higher HCV viral load was correlated with higher liver enzymes as well as lower BUP doses during the second and third trimester. These findings may be due to HCV related liver inflammation that potentially decreases liver clearance of BUP. Larger prospective studies as well as pharmacokinetic studies will be useful in further delineating this relationship.

Locomotor and anti-immobility effects of buprenorphine in combination with the opioid receptor modulator samidorphan in rats

Modulation of the opioid system has re-emerged as a potential therapeutic avenue for treating depression, with efficacy of a fixed-dose combination of buprenorphine (BUP), a partial μ-opioid receptor (MOR) agonist and κ-opioid receptor (KOR) antagonist, and samidorphan (SAM), a potent MOR antagonist, as an adjuvant treatment in patients with major depressive disorder (MDD). To advance understanding of the mechanism of action underlying this combination, we examined BUP, SAM and their combination in a series of rat behavioural assays. We examined effects on locomotor activity in Sprague Dawley (SD) rats over an extended period of time in a home-cage tracking system, and behavioural despair (immobility) in the forced swim test (FST), a commonly-used test to study antidepressants, in SD and Wistar-Kyoto (WKY) rats. Strain differences in opioid receptor and prepropeptide mRNA expression in the brain (prefrontal cortex, amygdala, hippocampus and striatum) were examined using qRT-PCR. BUP produced locomotor hyperactivity in SD rats from 2 to 6 h following administration, which was attenuated by SAM. In SD rats, a low, but not a high, dose of SAM in combination with BUP counteracted swim-stress induced immobility. This effect was not seen with BUP alone. In contrast, BUP alone reduced immobility in WKY rats, and this effect was enhanced by a low, but not high, dose of SAM. In WKY rats, MOR mRNA expression was higher in the hippocampus and lower in the striatum vs. SD rats. KOR mRNA expression was higher in the amygdala and nociceptin receptor (NOP) mRNA expression was lower in the hippocampus vs. SD rats. Differences in opioid receptor expression may account for the differential behavioural profile of WKY and SD rats. In summary, administration of BUP, a MOR receptor agonist together with a MOR opioid-receptor antagonist, SAM, reduces behavioural despair in animal models traditionally used to study effects of antidepressants.

Perioperative Management of Buprenorphine: Solving the Conundrum.

There is no consensus on the optimal perioperative management of patients on buprenorphine (BUP) for opioid use disorder (OUD). This article will review the available literature on BUP and the analgesic efficacy of BUP combined with full mu-opioid agonists and discuss the conflicting management strategies in the context of acute pain and our institution's protocol for the periprocedural management of BUP. We searched published data on BUP periprocedural management from inception through March 2018 without language restrictions. Study selection included publications reporting outcomes on perioperative pain management in OUD patients maintained on BUP. Our search resulted in four case reports supporting periprocedural discontinuation of BUP and two case series, one secondary observational study, one prospective matched cohort study, and four retrospective cohort studies supporting periprocedural continuation of BUP. No clinical trials were identified. Maintaining BUP perioperatively does not lead to worsened clinical outcomes. Patients can receive adequate pain control from mu-opioid agonists while maintained on BUP. Based upon available evidence, we recommend continuing BUP at a reduced dose when indicated to avoid withdrawal symptoms and to facilitate the analgesic efficacy of mu-opioid agonists administered in combination for acute postoperative pain.

In-vitro, ex-vivo, and in-vivo evaluation of buprenorphine HCl release from an in situ forming gel of PLGA-PEG-PLGA using N‑methyl‑2‑pyrrolidone as solvent

An in situ forming gel (ISFG) of buprenorphine (BP) was prepared using PLGA-PEG-PLGA (triblock) and N‑methyl‑2‑pyrrolidone as solvent for decreasing the initial burst release. Supercritical CO2 method was used for ring opening polymerization of triblock. The optimum formulation of ISFG was achieved based on a minimum initial burst release of BP in the in-vitro release media using Box-Behnken design. In-vitro, ex-vivo, and in-vivo studies of ISFG were compared with an in situ forming implant (ISFI) composed of copolymer PLGA 504H (similar to RBP-6000). The initial burst release from in vitro media for the ISFG (6.19 ± 0.31%) was significantly lower than that for the ISFI (13.45 ± 1.14%) because the thermosensitive property of the triblock and hydrogen bonding between the NMP molecules and the PEG of the triblock prevented the NMP from diffusing rapidly into the release medium. The Cmax of BP (6.95 ± 0.98 ng/mL) from the ISFG was significantly (p < 0.05) lower than those from the ISFI (8.19 ± 1.02). Furthermore, the AUC, the range of serum concentration (C) of BP for the ISFG (AUC = 2721.38 ± 69, C = 1.87–7.12) formulation were similar to those for ISFI (AUC = 2727.36 ± 71, C = 1.75–10). The results suggest that the ISFG can be used as a new type of sustained-release injection formulation with a smaller initial burst release than the ISFI.

Opioid system modulators buprenorphine and samidorphan alter behavior and extracellular neurotransmitter concentrations in the Wistar Kyoto rat

Approximately two-thirds of major depressive disorder (MDD) patients do not respond adequately to current therapies. BUP/SAM (ALKS 5461), a combination of buprenorphine (BUP) and samidorphan (SAM), is a novel opioid system modulator in development as an adjunct treatment for MDD. Using a rat strain (Wistar Kyoto rat) that is predisposed to stress and has an inadequate response to selective serotonin reuptake inhibitors (SSRIs), we investigated the effect of BUP and SAM, individually and in combination, in established nonclinical assays used to study antidepressants (the forced swim test, FST) and anxiolytics (marble burying test). As opioids and their receptors are expressed in mesocorticolimbic regions of the brain, we analyzed extracellular concentrations of dopamine, serotonin, and/or their metabolites in brain areas associated with mood and motivation. BUP alone and in combination with SAM significantly reduced immobility in the FST. Similarly, the BUP/SAM combination significantly reduced immobility in SSRI (escitalopram)-treated rats. BUP/SAM also decreased burying behavior. SAM attenuated BUP-induced changes of extracellular levels of serotonin and dopamine in the medial prefrontal cortex and nucleus accumbens shell. The latter suggests that the addition of SAM to BUP may limit activation of the mesolimbic dopamine reward pathway and thereby reduce BUP's reinforcing properties. SAM alone had no effect on neurochemistry or immobility in the FST. Collectively, these data indicate that opioid system modulation may offer an alternative mechanism that does not rely on enhanced serotonergic neurotransmission in neurocircuits associated with antidepressant and anxiolytic activity in nonclinical models.