Search

Buprenorphine, a novel opioid with complex pharmacology, is effective for treating pain and is qualitatively safer than high-dose full agonist opioid therapy; but transitioning to buprenorphine can be technically complex and carries some risk of precipitated withdrawal. We report our clinic's experience converting 36 patients with sickle cell disease (SCD) from full agonist opioids to buprenorphine using a method developed in the past 10 years. Thirty of these patients were induced using a standard outpatient protocol and six were induced during medical admissions. Typically, patients were on high-dose chronic opioid therapy (COT) with inadequate response, and often with very high acute care utilization. Unlike prior case series, the method of induction, dosing, and management of withdrawal are detailed, as are post-induction adverse events. There were seven adverse events in the first 3 days following standard induction, and two of which were judged to be definitely related to the induction but none with any lasting sequelae. At 6 months follow-up, five participants had discontinued buprenorphine (16.67%), and overall acute care visits dropped from a mean of 10.50 (SD 11.35) in the 6 months pre-induction to 2.89 (SD 3.40) in the 6 months post-induction. In an appropriately interdisciplinary care setting, buprenorphine shows promise as a safe alternative to COT with early evidence of benefit for high-utilizing patients with SCD., (© 2022 Wiley Periodicals LLC.)

Introduction: Current WHO guidelines recommend using methadone or buprenorphine as maintenance treatments for maternal opioid use disorder. However, buprenorphine‐naloxone, with a lower abuse risk than buprenorphine monotherapy or methadone, offers a potentially beneficial alternative, but scientific evidence on its effects on pregnancies, fetuses, and newborns is scarce. This paper compares the outcomes of the pregnancies, deliveries, and newborns of women on buprenorphine‐naloxone, buprenorphine, or methadone maintenance treatments. According to the hypothesis, as a maintenance treatment, buprenorphine‐naloxone does not have more adverse effects than buprenorphine, whereas methadone is more complicated. Material and methods: In this population‐based study, 172 pregnant women on medical‐assisted treatments were followed‐up at Helsinki University Women's Hospital (Finland). Women receiving the same opioid maintenance treatment from conception to delivery and their newborns were included. Consequently, 67 mother–child dyads met the final inclusion criteria. They were divided into three groups based on their opioid pharmacotherapy. The outcomes were compared among the groups and, where applicable, with the Finnish population. Results: The buprenorphine‐naloxone and buprenorphine groups showed similar outcomes and did not significantly differ from each other in terms of maternal health during pregnancies, deliveries, or newborns. Illicit drug use during the pregnancy was common in all groups, but in the methadone group it was most common (p = 0.001). Most neonates (96%) were born full‐term with good Apgar scores. They were of relatively small birth size, with those in the methadone group tending to be the smallest. Of the neonates 63% needed pharmacological treatment for neonatal opioid withdrawal syndrome. The need was lower in the buprenorphine‐based groups than in the methadone group (p = 0.029). Conclusions: Buprenorphine‐naloxone seems to be as safe for pharmacotherapy for maternal opioid use disorder as buprenorphine monotherapy for both mother and newborn. Hence it could be a choice for oral opioid maintenance treatment during pregnancy, but larger studies are needed before changing the official recommendations. Women on methadone treatment carry multifactorial risks and require particularly cautious follow up. Furthermore, illicit drug use is common in all treatment groups and needs to be considered for all patients with opioid use disorder. [ABSTRACT FROM AUTHOR]

Aim: Although studies in Western countries have investigated the quality of life (QoL) of heroin users, limited research on this topic has been conducted in Asia. The present study assessed QoL in patients with heroin dependence receiving medications to treat opioid use disorder. Methods: We performed a cross‐sectional study of patients with heroin dependence receiving methadone and buprenorphine treatment. The demographic and substance use variables of patients receiving methadone and buprenorphine were compared. The Chinese Health Questionnaire (CHQ‐12), Obsessive Compulsive Drug Use Scale (OCDUS), and World Health Organization Quality of Life Short Form Taiwan version (WHOQOL‐BREF‐T) were administered to measure patient mental health problems, addiction severity, and QoL, respectively. Multivariate regression was used to identify the factors associated with QoL. Results: A total of 149 patients receiving methadone and 31 receiving buprenorphine completed the questionnaires. Individuals in the buprenorphine group were more likely to be married (p = 0.024) or employed (p = 0.024), have a higher educational level (p = 0.013), have lower drug craving (OCDUS: p = 0.035), or have higher QoL (WHOQOL‐BREF‐T: p = 0.004) than those in the methadone group. After adjustment for other variables, employment was positively associated with the physical, psychological, and environmental domains of QoL. Receiving buprenorphine treatment (p = 0.032) and longer treatment duration (p = 0.016) were associated with higher psychological QoL. Conclusion: Several factors were associated with QoL in patients with heroin dependence. Some measures may improve their QoL, such as reducing employment barriers, improving treatment adherence, or increasing accessibility to buprenorphine treatment. [ABSTRACT FROM AUTHOR]

Background: People who use drugs (PWUD) frequently delay or avoid obtaining medical care in traditional healthcare settings. Through a randomized controlled trial, we investigated facilitated telemedicine for hepatitis C virus (HCV) integrated into opioid treatment programmes. We sought to understand the experiences and meanings of facilitated telemedicine and an HCV cure among PWUD. Methods: We utilized purposive sampling to interview 25 participants, 6–40 months after achieving an HCV cure. We interpreted and explicated common meanings of participants' experiences of an HCV cure obtained through facilitated telemedicine. Results: Participants embraced facilitated telemedicine integrated into opioid treatment programmes as patient‐centred care delivered in 'safe spaces' (Theme 1). Participants elucidated their experiences of substance use and HCV while committing to treatment for both entities. Facilitated telemedicine integrated into opioid treatment programmes enabled participants to avoid stigma encountered in conventional healthcare settings (Theme 2). Participants conveyed facing negative perceptions of HCV and substance use disorder. Improved self‐awareness, acquired through HCV and substance use treatment, enabled participants to develop strategies to address shame and stigma (Theme 3). An HCV cure, considered by PWUD as a victory over a lethal infectious disease, promotes self‐confidence, enabling participants to improve their health and lives (Theme 4). Conclusions: Integrating facilitated telemedicine into opioid treatment programmes addresses several healthcare barriers for PWUD. Similarly, obtaining an HCV cure increases their self‐confidence, permissive to positive lifestyle changes and mitigating the negative consequences of substance use. Patient and Public Contribution: In this study of patient involvement, we interviewed patient‐participants to understand the meaning of an HCV cure through facilitated telemedicine. Participants from a facilitated telemedicine pilot study provided essential input on the design and outcomes of a randomized controlled trial. Pilot study participants endorsed facilitated telemedicine in a testimonial video. They attended site initiation meetings to guide trial implementation. A Patient Advisory Committee (PAC) ensured that patient participants were active members of the research team. The PAC represented patients' voices through feedback on study procedures. A Sustainability Committee supported public involvement in the research process, including educational opportunities, feedback on implementation, and future sustainability considerations. [ABSTRACT FROM AUTHOR]

Introduction Ukraine's volatile HIV epidemic, one of the largest in Eastern Europe and Central Asia, remains concentrated in people who inject drugs (PWID). HIV prevalence is high (21.3% to 41.8%) among the estimated 310,000 PWID. Opioid agonist therapy (OAT) is the most cost-effective HIV prevention strategy there, yet OAT services are hampered by negative attitudes and frequent harassment of OAT clients and site personnel by law enforcement. This paper examines the various types of police violence that Ukrainian PWID experience and factors associated with the different types of violence, as well as the possible implications of police harassment on OAT retention. Methods In 2014 to 2015, we conducted a cross-sectional survey in five Ukrainian cities with 1613 PWID currently, previously and never on OAT, using a combination of respondent-driven sampling, as well as random sampling. We analysed correlates of police violence by multiple factors, including by gender, and their effects on duration of OAT retention. Self-reported physical and sexual violence by police were the two primary outcomes, while retention on OAT was used as a secondary outcome. Results Overall, 1033 (64.0%) PWID reported being physically assaulted by police, which was positively correlated with currently or previously being on OAT (69.1% vs. 60.2%; p<0.01). HIV prevalence rates were higher in those receiving OAT than those not on OAT (47.6% vs. 36.1%; p<0.01). Police violence experiences differed by sex, with men experiencing significantly more physical violence, while women experienced more sexual violence (65.9% vs. 42.6%; p<0.01). For PWID who had successfully accessed OAT, longer OAT retention was significantly correlated both with sexual assault by police and fewer non-fatal overdoses. Conclusions Police violence is a frequent experience among PWID in Ukraine, particularly for those accessing OAT, an evidence-based primary and secondary HIV prevention strategy. Police violence experiences, however, were different for men and women, and interventions with police that address these sexual differences and focus on non-violent interactions with PWID to improve access and retention on OAT are crucial for improving HIV prevention and treatment goals for Ukraine. [ABSTRACT FROM AUTHOR]

Opioid overdose remains a problem in the United States despite pharmacotherapies, such as buprenorphine, in the treatment of opioid use disorder. This study characterized changes in buprenorphine use. Using the Drug Enforcement Administration's ARCOS, Medicaid, and Medicare claims databases, patterns in buprenorphine usage in the United States from 2018 to 2020 were analyzed by examining percentage changes in total grams distributed and changes in grams per 100 K people in year‐to‐year usage based on ZIP code and state levels. For ARCOS from 2018 to 2019 and 2019 to 2020, total buprenorphine distribution in grams increased by 16.2% and 12.6%, respectively. South Dakota showed the largest statewide percentage increase in both 2018–2019 (66.1%) and 2019–2020 (36.7%). From 2018 to 2019, the ZIP codes ND‐577 (156.4%) and VA‐222 (−82.1%) had the largest and smallest percentage changes, respectively. From 2019 to 2020, CA‐932 (250.2%) and IL‐603 (−36.8%) were the largest and smallest, respectively. In both 2018–2019 and 2019–2020, PA‐191 had the second highest increase in grams per 100K while OH‐452 was the only ZIP code to remain in the top three largest decreases in grams per 100K in both periods. Among Medicaid patients in 2018, there was a nearly 2000‐fold difference in prescriptions per 100k Medicaid enrollees between Kentucky (12 075) and Nebraska (6). Among Medicare enrollees in 2018, family medicine physicians and other primary care providers were the top buprenorphine prescribers. This study not only identified overall increases in buprenorphine availability but also pronounced state‐level differences. Such geographic analysis can be used to discern which public policies and regional factors impact buprenorphine access. [ABSTRACT FROM AUTHOR]

Aims: Buprenorphine is effective at reducing relapse to opioid misuse, morbidity and mortality in opioid‐dependent patients. Urine drug screening (UDS) to assess adherence is used routinely in opioid agonist treatment (OAT). The primary aim of this study was to determine factors which may be associated with a negative qualitative urine drug screen for buprenorphine in OAT patients. Methods: This prospective pilot study was conducted at a tertiary addiction medicine centre. Twenty participants on stable treatment underwent supervised administration of sublingual buprenorphine. Matched urine and blood samples were collected prior to and 2, 4 and 6 hours after buprenorphine administration. Qualitative urine drug screen results were obtained using gas chromatography–mass spectrometry (GC–MS), while quantitative blood and urine results were obtained using ultra‐performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS). Results: Qualitative urine assay yielded a negative result for buprenorphine in 57% of tested samples. The median concentration of urinary buprenorphine was 167 mcg/L (range: 2–1730 mcg/L). Thirty percent of all blood samples did not detect buprenorphine (range 0–18 mcg/L). Positive qualitative urine drug screen results were associated with higher urine (343 mcg/L compared with 75 mcg/L; P <.05) and blood (4 mcg/L compared with 2 mcg/L; P <.05) buprenorphine concentrations. Median urine concentrations of buprenorphine were highest at 2 hours and were higher in participants receiving CYP3A4 inhibitors. Conclusion: Interpretation of qualitative urine drug screens to assess adherence in OAT is complex. Poor adherence with treatment cannot be assumed in patients returning a negative qualitative GC–MS urine drug screen. [ABSTRACT FROM AUTHOR]

Understanding how pharmaceutical opioids and antipyretic analgesics interact with the immune system potentially has major clinical implications for management of patients with infectious diseases and surgical and critical care patients. An electronic search was carried out on MEDLINE, EMBASE, PsycINFO, CENTRAL and the Cochrane library to identify reports describing the immunomodulatory effects of opioid analgesics and antipyretic analgesics, and their effects in infectious diseases. In adaptive immunity, nonsteroidal anti‐inflammatory drugs have divergent effects: augmenting cell‐mediated immunity but inhibiting humoral immunity. Nonsteroidal anti‐inflammatory drugs have demonstrated a beneficial role in Mycobacterium tuberculosis infection and histoplasmosis in animals, and may be plausible adjuvants to antimicrobial agents in these diseases. There is a need to evaluate these findings rigorously in human clinical trials. There is preliminary evidence demonstrating antiviral effects of indomethacin in SARS CoV‐2 in vitro; however, uncertainty regarding its clinical benefit in humans needs to be resolved in large clinical trials. Certain opioid analgesics are associated with immunosuppressive effects, with a developing understanding that fentanyl, morphine, methadone and buprenorphine suppress innate immunity, whilst having diverse effects on adaptive immunity. Morphine suppresses key cells of the innate immunity and is associated with greater risk of infection in the postsurgical setting. Efforts are needed to achieve adequate analgesia whilst avoiding suppression of the innate immunity in the immediate postoperative period caused by certain opioids, particularly in cancer surgery. [ABSTRACT FROM AUTHOR]

Objectives: The objective was to describe emergency medicine (EM) resident attitudes, preferences, and experiences around the knowledge and skills around the evidence‐based treatment of opioid use disorder (OUD) in the emergency department (ED). Methods: We created an online survey that was distributed by the Emergency Medicine Residents' Association research committee listserv to approximately 6600 resident physicians at all levels of EM residency training. Data were collected between June 2020 and October 2020. This 12‐question voluntary, anonymous survey included questions exploring EM resident preferences and experiences around the education and exposure to the evidence‐based management of patients with OUD in the ED setting. Descriptive statistics were used. Results: A total of 288 of 6600 invited EM residents (response rate 4.4%) from 127 different EM residency programs across 38 states in the United States, District of Columbia, and Puerto Rico completed the survey. Most respondents (165/288; 57.3%) reported that it was "very important" for emergency physicians to have training to initiate buprenorphine treatment for patients with OUD. Just under half (140/288; 48.6%) reported they have or will receive X‐waiver training during residency and 46.9% (135/288) reported experience prescribing buprenorphine in the ED. The estimated proportions of EM faculty at responding residents' primary teaching hospital with an X‐waiver was "most or all" (48/285; 16.8%), "about half" (23/285; 8.1%), "a handful" (79/285; 27.7%), "one or two" (33/285; 11.6%), "none" (19/285; 6.7%), or "not sure" (83/285; 29.1%). Conclusion: Survey results suggest that resident emergency physicians perceive the evidence‐based management of OUD to be relevant to EM residency training and are interested in receiving training on initiating medications for OUD treatment in the ED. Opportunities to improve resident education and clinical use of buprenorphine during ED residency training were identified. [ABSTRACT FROM AUTHOR]

The article discusses research that explored perspectives and experiences of patients with opioid use disorder (OUD) and using medications for OUD recruited in a single tertiary care emergency department in Massachusetts. Topics covered include decisional needs and factors relevant for decision making, informing decision support, and recovery/relapse.

Background and Purpose: Maintenance treatment with opioid agonists (buprenorphine, methadone) decreases opioid use and relapse. We recently modelled maintenance treatment in rats and found that chronic delivery of buprenorphine or the μ opioid receptor partial agonist TRV130 decreased relapse to oxycodone seeking and taking. Here, we tested the buprenorphine analogue BU08028 on different heroin relapse‐related measures and heroin versus food choice. Experimental Approach For relapse assessment, we trained male and female rats to self‐administer heroin (6 h·day−1, 14 days) in Context A and then implanted osmotic minipumps containing BU08028 (0, 0.03 or 0.1 mg·kg−1·d−1). Effects of chronic BU08028 delivery were tested on (1) incubation of heroin‐seeking in a non‐drug Context B, (2) extinction responding reinforced by heroin‐associated discrete cues in Context B, (3) reinstatement of heroin‐seeking induced by re‐exposure to Context A and (4) re‐acquisition of heroin self‐administration in Context A. For choice assessment, we tested the effect of chronic BU08028 delivery on heroin versus food choice. Key Results: Chronic BU08028 delivery decreased incubation of heroin seeking. Unexpectedly, BU08028 increased re‐acquisition of heroin self‐administration selectively in females. Chronic BU08028 had minimal effects on context‐induced reinstatement and heroin versus food choice in both sexes. Finally, exploratory post hoc analyses suggest that BU08028 decreased extinction responding selectively in males. Conclusions and Implications: Chronic BU08028 delivery had both beneficial and detrimental, sex‐dependent, effects on different triggers of heroin relapse and minimal effects on heroin choice in both sexes. Results suggest that BU08028 would not be an effective opioid maintenance treatment in humans. [ABSTRACT FROM AUTHOR]

Objectives: Despite evidence demonstrating the safety and efficacy of buprenorphine for the treatment of emergency department (ED) patients with opioid use disorder (OUD), incorporation into clinical practice has been highly variable. We explored barriers and facilitators to the prescription of buprenorphine, as perceived by practicing ED clinicians. Methods: We conducted semistructured interviews with a purposeful sample of ED clinicians. An interview guide was developed using the Consolidated Framework for Implementation Research and Theoretical Domains Framework implementation science frameworks. Interviews were recorded, transcribed, and analyzed in an iterative process. Emergent themes were identified, discussed, and organized. Results: We interviewed 25 ED clinicians from 11 states in the United States. Participants were diverse with regard to years in practice and practice setting. While outer setting barriers such as the logistic costs of getting a DEA‐X waiver and lack of clear follow‐up for patients were noted by many participants, individual‐level determinants driven by emotion (stigma), beliefs about consequences and roles, and knowledge predominated. Participants' responses suggested that implementation strategies should address stigma, local culture, knowledge gaps, and logistic challenges, but that a particular order to addressing barriers may be necessary. Conclusions: While some participants were hesitant to adopt a "new" role in treating patients with medications for OUD, many already had and gave concrete strategies regarding how to encourage others to embrace their attitude of "this is part of emergency medicine now." [ABSTRACT FROM AUTHOR]

Objectives: The opioid crisis has risen dramatically in North America in the new millennium, due to both illegal and prescription opioid use. While emergency departments (EDs) represent a potentially strategic setting for interventions to reduce harm from opioid use disorder (OUD), the absence of a recent synthesis of literature limits implementation and scalability. To fill this gap, we conducted a systematic review of the literature on interventions targeting OUDs initiated in EDs. Methods: Using an explicit search strategy (PROSPERO), the MEDLINE, CINAHL Complete, EMBASE, and EBM reviews databases were searched from 1980 to October 4, 2019. The gray literature was explored using Google Scholar. Study characteristics were abstracted independently. The methodologic quality and risk of bias were assessed. Results: Twelve of 2,270 studies met the inclusion criteria (two of high quality). In addition to the heterogeneity of the outcome measures used (retention in treatment, opioid consumption, and overdose), brief intervention and buprenorphine initiation (six of 12 studies) were the most documented with mixed effects for the former and positive short‐term and confined to single ED sites effects for the latter. Conclusion: Emergency departments can be an appropriate setting for initiating opioid agonist treatment, but to be sustained, it likely needs to be coupled with community‐based follow‐up and support to ensure longer‐term retention. The scarcity of high‐quality evidence on OUD interventions initiated in emergency settings highlights the need for future research. [ABSTRACT FROM AUTHOR]

Aims: Oral opioid preparations combined with naloxone are intended to induce a transient acute withdrawal syndrome to avoid intravenous misuse. This trial aimed to establish an appropriate morphine–naloxone dose ratio for an abuse‐deterrent oral opioid formulation. Methods: In a randomized, double‐blinded, 2 × 2 cross‐over trial, 43 patients with opioid use disorder were challenged with intravenous morphine HCl Ph.Eur. (75 mg; [morphine mono]) or morphine HCl Ph.Eur. and naloxone HCl Ph.Eur. at ratios of 100:1 (75 mg: 0.75 mg; [morphine–naloxone 100:1]) or 200:1 (75 mg: 0.375 mg; [morphine–naloxone 200:1]). Acute naloxone‐induced opioid withdrawal was evaluated using subjective (Short Opiate Withdrawal Scale–German [SOWS‐G]) and observer‐rated (Objective Opiate Withdrawal Scale [OOWS], Wang scale) questionnaires, and physiological parameters. For statistical analysis, the area under the curve between baseline and 20 minutes after drug administration of the outcome variables was calculated. Results: Intravenous morphine–naloxone caused rapid withdrawal symptoms. Coadministration of naloxone dose‐dependently (morphine–naloxone 100:1 > morphine–naloxone 200:1) increased SOWS‐G, OOWS and Wang Scale area under the curve when compared to morphine mono, respectively (all P <.0001). A similar response was detectable for changes of pupil diameter. Blood pressure and respiratory rate changed heterogeneously, and heart rate was unaltered by morphine without or with naloxone. Conclusion: Morphine–naloxone 100:1 effectively suppresses the pleasurable effects of intravenous morphine and results in an aversive withdrawal reaction. A lower naloxone concentration as used in morphine–naloxone 200:1 does not appear to be appropriate to prevent intravenous morphine misuse. [ABSTRACT FROM AUTHOR]

Objectives: Adoption of emergency department (ED) initiation of buprenorphine (BUP) for opioid use disorder (OUD) into routine emergency care has been slow, partly due to clinicians' unfamiliarity with this practice and perceptions that it is complicated and time‐consuming. To address these barriers and guide emergency clinicians through the process of BUP initiation, we implemented a user‐centered computerized clinical decision support system (CDS). This study was conducted to assess the feasibility of implementation and to evaluate the preliminary efficacy of the intervention to increase the rate of ED‐initiated BUP. Methods: An interrupted time series study was conducted in an urban, academic ED from April 2018 to February 2019 (preimplementation phase), March 2019 to August 2019 (implementation phase), and September 2019 to December 2019 (maintenance phase) to study the effect of the intervention on adult ED patients identified by a validated electronic health record (EHR)‐based computable phenotype consisting of structured data consistent with potential cases of OUD who would benefit from BUP treatment. The intervention offers flexible CDS for identification of OUD, assessment of opioid withdrawal, and motivation of readiness to start treatment and automates EHR activities related to ED initiation of BUP (including documentation, orders, prescribing, and referral). The primary outcome was the rate of ED‐initiated BUP. Secondary outcomes were launch of the intervention, prescription for naloxone at ED discharge, and referral for ongoing addiction treatment. Results: Of the 141,041 unique patients presenting to the ED over the preimplementation and implementation phases (i.e., the phases used in primary analysis), 906 (574 preimplementation and 332 implementation) met OUD phenotype and inclusion criteria. The rate of BUP initiation increased from 3.5% (20/574) in the preimplementation phase to 6.6% (22/332) in the implementation phase (p = 0.03). After the temporal trend of the number of physician's with X‐waiver training and other covariates were adjusted for, the relative risk of BUP initiation rate was 2.73 (95% confidence interval [CI] = 0.62 to 12.0, p = 0.18). Similarly, the number of unique attendings who initiated BUP increased modestly 7/53 (13.0%) to 13/57 (22.8%, p = 0.10) after offering just‐in‐time training during the implementation period. The rate of naloxone prescribed at discharge also increased (6.5% preimplementation and 11.5% implementation; p < 0.01). The intervention received a system usability scale score of 82.0 (95% CI = 76.7 to 87.2). Conclusion: Implementation of user‐centered CDS at a single ED was feasible, acceptable, and associated with increased rates of ED‐initiated BUP and naloxone prescribing in patients with OUD and a doubling of the number of unique physicians adopting the practice. We have implemented this intervention across several health systems in an ongoing trial to assess its effectiveness, scalability, and generalizability. [ABSTRACT FROM AUTHOR]

Summary: A growing body of evidence has indicated that the release of nociceptive factors, such as interleukins and chemokines, by activated immune and glial cells has crucial significance for neuropathic pain generation and maintenance. Moreover, changes in the production of nociceptive immune factors are associated with low opioid efficacy in the treatment of neuropathy. Recently, it has been suggested that CC chemokine receptor type 1 (CCR1) signaling is important for nociception. Our study provides evidence that the development of hypersensitivity in rats following chronic constriction injury (CCI) of the sciatic nerve is associated with significant up‐regulation of endogenous CCR1 ligands, namely, CCL2, CCL3, CCL4, CCL6, CCL7 and CCL9 in the spinal cord and CCL2, CCL6, CCL7 and CCL9 in dorsal root ganglia (DRG). We showed that single and repeated intrathecal administration of J113863 (an antagonist of CCR1) attenuated mechanical and thermal hypersensitivity. Moreover, repeated administration of a CCR1 antagonist enhanced the analgesic properties of morphine and buprenorphine after CCI. Simultaneously, repeated administration of J113863 reduced the protein levels of IBA‐1 in the spinal cord and MPO and CD4 in the DRG and, as a consequence, the level of pronociceptive factors, such as interleukin‐1β (IL‐1β), IL‐6 and IL‐18. The data obtained provide evidence that CCR1 blockade reduces hypersensitivity and increases opioid‐induced analgesia through the modulation of neuroimmune interactions. [ABSTRACT FROM AUTHOR]

Aims: The present study assessed the acute effects of methadone and buprenorphine on actual on‐road driving performance and neurocognitive function. Methods: Methadone (5 and 10 mg per os) and buprenorphine (0.2 and 0.4 mg sublingual) were administered to 22 healthy volunteers in a five‐way, double‐blind, randomized, placebo‐controlled, double‐dummy, cross‐over study. Driving performance was assessed with an on‐road driving test. The primary outcome measure was standard deviation of lateral position (SDLP), a measure of road tracking control. Laboratory tests were used to measure cognitive function (e.g. reaction time and attention) and questionnaires were used to assess subjective measures of mood and sedation. Results: There was no significant main effect of treatment on SDLP. Yet, analysis of individual drug‐placebo contrast data revealed that buprenorphine 0.4 mg significantly increased SDLP. Driving impairment was mild and below the impairment threshold of a blood alcohol concentration of 0.5 mg ml−1. Four participants stopped their driving test while under the influence of either opioid due to sleepiness. Both opioids produced impairments of cognitive task performance and increased sleepiness particularly at the highest dose. Conclusions: Analgesic doses of buprenorphine produced mild impairing effects on driving and related cognitive skills, while methadone impaired cognitive task performance but not driving performance. Large individual variations were observed for both drugs. Patients should be informed about the possibility of driving impairment when initiating opioid treatment. [ABSTRACT FROM AUTHOR]

Background and Purpose: The κ receptor antagonists have potential for treating neuropsychiatric disorders. We have investigated the in vivo pharmacology of a novel buprenorphine analogue, BU10119, for the first time. Experimental Approach: To determine the opioid pharmacology of BU10119 (0.3–3 mg·kg−1, i.p.) in vivo, the warm‐water tail‐withdrawal assay was applied in adult male CD1 mice. A range of behavioural paradigms was used to investigate the locomotor effects, rewarding properties and antidepressant or anxiolytic potential of BU10119. Additional groups of mice were exposed to a single (1 × 2 h) or repeated restraint stress (3× daily 2 h) to determine the ability of BU10119 to block stress‐induced analgesia. Key Results: BU10119 alone was without any antinociceptive activity. BU10119 (1 mg·kg−1) was able to block U50,488, buprenorphine and morphine‐induced antinociception. The κ antagonist effects of BU10119 in the tail‐withdrawal assay reversed between 24 and 48 h. BU10119 was without significant locomotor or rewarding effects. BU10119 (1 mg·kg−1) significantly reduced the latency to feed in the novelty‐induced hypophagia task and reduced immobility time in the forced swim test, compared to saline‐treated animals. There were no significant effects of BU10119 in either the elevated plus maze or the light–dark box. Both acute and repeated restraint stress‐induced analgesia were blocked by pretreatment with BU10119 (1 mg·kg−1). Parallel stress‐induced increases in plasma corticosterone were not affected. Conclusions and Implications: BU10119 is a mixed κ/μ receptor antagonist with relatively short‐duration κ antagonist activity. Based on these preclinical data, BU10119 has therapeutic potential for the treatment of depression and other stress‐induced conditions. Linked Articles: This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc [ABSTRACT FROM AUTHOR]

Growing evidence has indicated that opioids enhance replication of human immunodeficiency virus and hepatitis C virus in target cells. However, it is unknown whether opioids can enhance replication of other clinically important viral pathogens. In this study, the interaction of opioid agonists and human influenza A/WSN/33 (H1N1) virus was examined in human lung epithelial A549 cells. Cells were exposed to morphine, methadone or buprenorphine followed by human H1N1 viral infection. Exposure to methadone differentially enhanced viral propagation, consistent with an increase in virus adsorption, susceptibility to virus infection and viral protein synthesis. In contrast, morphine or buprenorphine did not alter H1N1 replication. Because A549 cells do not express opioid receptors, methadone-enhanced H1N1 replication in human lung cells may not be mediated through these receptors. The interaction of methadone and H1N1 virus was also examined in adult mice. Treatment with methadone significantly increased H1N1 viral replication in lungs. Our data suggest that use of methadone facilitates influenza A viral infection in lungs and might raise concerns regarding the possible consequence of an increased risk of serious influenza A virus infection in people who receive treatment in methadone maintenance programs. [ABSTRACT FROM AUTHOR]

Background and Purpose For patients experiencing inadequate analgesia and intolerable opioid-related side effects on one strong opioid analgesic, pain relief with acceptable tolerability is often achieved by rotation to a second strong opioid. These observations suggest subtle pharmacodynamic differences between opioids in vivo. This study in rats was designed to assess differences between opioids in their in vivo profiles. Experimental Approach Male Sprague Dawley rats were given single i.c.v. bolus doses of morphine, morphine-6-glucuronide ( M6G), fentanyl, oxycodone, buprenorphine, DPDPE ([D-penicillamine2,5]-enkephalin) or U69,593. Antinociception, constipation and respiratory depression were assessed using the warm water tail-flick test, the castor oil-induced diarrhoea test and whole body plethysmography respectively. Key Results These opioid agonists produced dose-dependent antinociception, constipation and respiratory depression. For antinociception, morphine, fentanyl and oxycodone were full agonists, buprenorphine and M6G were partial agonists, whereas DPDPE and U69,593 had low potency. For constipation, M6G, fentanyl and buprenorphine were full agonists, oxycodone was a partial agonist, morphine produced a bell-shaped dose-response curve, whereas DPDPE and U69,593 were inactive. For respiratory depression, morphine, M6G, fentanyl and buprenorphine were full agonists, oxycodone was a partial agonist, whereas DPDPE and U69,593 were inactive. The respiratory depressant effects of fentanyl and oxycodone were of short duration, whereas morphine, M6G and buprenorphine evoked prolonged respiratory depression. Conclusion and Implications For the seven opioids we assessed, no two had the same profile for evoking antinociception, constipation and respiratory depression, suggesting that these effects are differentially regulated. Our findings may explain the clinical success of 'opioid rotation'. Linked Articles This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit [ABSTRACT FROM AUTHOR]

Background and Purpose There is significant variation in individual response to opioid drugs, which may result in inappropriate opioid therapy. Polymorphisms of the μ opioid receptor ( MOP receptor) may contribute to individual variation in opioid response by affecting receptor function, and the effect may be ligand-specific. We sought to determine functional differences in MOP receptor signalling at several signalling pathways using a range of structurally distinct opioid ligands in cells expressing wild-type MOP receptors ( MOPr- WT) and the commonly occurring MOP receptor variant, N40 D. Experimental Approach MOPr- WT and MOPr- N40 D were stably expressed in CHO cells and in At T-20 cells. Assays of AC inhibition and ERK1/2 phosphorylation were performed on CHO cells, and assays of K activation were performed on At T-20 cells. Signalling profiles for each ligand were compared between variants. Key Results Buprenorphine efficacy was reduced by over 50% at MOPr- N40 D for AC inhibition and ERK1/2 phosphorylation. Buprenorphine potency was reduced threefold at MOPr- N40 D for K channel activation. Pentazocine efficacy was reduced by 50% for G-protein-gated inwardly rectifying K channel activation at MOPr- N40 D. No other differences were observed for any other ligands tested. Conclusions and Implications The N40 D variant is present in 10-50% of the population. Buprenorphine is a commonly prescribed opioid analgesic, and many individuals do not respond to buprenorphine therapy. This study demonstrates that buprenorphine signalling to several effectors via the N40 D variant of MOP receptors is impaired, and this may have important consequences in a clinical setting for individuals carrying the N40 D allele. [ABSTRACT FROM AUTHOR]

Heroin use among young women of reproductive age has drawn much attention around the world. However, there is lack of information on the long-term effects of prenatal exposure to opioids on their offspring. Our previous study demonstrated that prenatally buprenorphine-exposed offspring showed a marked change in the cross-tolerance to morphine compared with other groups. In the current study, this animal model was used to study effects of methamphetamine ( METH)-induced behavioral sensitization in the offspring at their adulthood. The results showed no differences in either basal or acute METH-induced locomotor activity in any of the groups of animals tested. When male offspring received METH injections of 2 mg/kg, i.p., once a day for 5 days, behavioral sensitization was induced, as determined by motor activity. Furthermore, the distance and rate of development (slope) of locomotor activity and conditioned place preference induced by METH were significantly increased in the prenatally buprenorphine-exposed animals compared with those in other groups. The dopamine D1R in the nucleus accumbens of the prenatally buprenorphine-exposed offspring had lower mRNA expression; but no significant changes in the μ-, κ-opioid, nociceptin, D2R and D3R receptors were noted. Furthermore, significant alterations were observed in the basal level of cAMP and the D1R agonist enhanced adenylyl cyclase activity in the prenatally buprenorphine-exposed group. Overall, the study demonstrates that D1R and its downregulated cAMP signals are involved in enhancing METH-induced behavioral sensitization in prenatally buprenorphine-exposed offspring. The study reveals that prenatal exposure to buprenorphine caused long-term effects on offspring and affected the dopaminergic system-related reward mechanism. [ABSTRACT FROM AUTHOR]

Key Clinical Message A 20-year-old indigenous Australian male was admitted to the intensive care unit with fulminant hepatic failure secondary to intravenous use of buprenorphine, which had been prescribed sublingually for opioid dependence. Intravenous buprenorphine-induced hepatitis is well recognized, however, life-threatening fulminant hepatic failure has not previously been reported. [ABSTRACT FROM AUTHOR]