Pharmacotherapy For Opioid Use Disorder Research Articles

Attitudes and Subjective Norms Regarding Medication for Opioid Use Disorder Among Individuals in Treatment for Opioid Use Disorder in the Greater St. Louis Area

Medication for opioid use disorder (MOUD) is safe and efficacious for treating opioid use disorder (OUD), yet there is limited understanding of how attitudes and subjective norms regarding MOUD among individuals with OUD may impede treatment uptake. Thus, the current study describes attitudes and subjective norms in a sample of individuals with OUD in the St. Louis area ( N = 183) and compares outcomes among those who were and were not actively taking MOUD. Most endorsed positive views regarding pharmacologic treatment for OUD overall, but concerns about physical side effects, the daily nature of some MOUD options, and uncertainty about the relative risks and benefits of MOUD remained prevalent. Individuals reporting current MOUD use had more accepting attitudes and perceived subjective norms regarding MOUD compared to others, suggesting that interventions targeting improvements in the knowledge of, attitudes toward, and normalization of MOUD are needed to further improve uptake and retention in pharmacotherapy for OUD.

Race, rurality and geographic accessibility to medication for opioid use disorder in the U.S.

ABSTRACT Disparities in geographic access to medication for opioid use disorder (OUD) are well documented. Further, historical implications of systemic racism and of the longstanding War on Drugs in the United States have driven both social and spatial inequities in access to treatment. This work builds on a previously published spatial access methodology that uses a gravity-based variant of the enhanced two-step floating catchment area model, to determine how OUD pharmacotherapy accessibility varies nationally at the census tract level. Medication for OUD (MOUD) accessibility scores are then analyzed by rurality and racial/ethnic segregation. The Getis-Ord Gi* statistic was used to identify clusters of high or low accessibility to MOUD, while the interaction index was used as a measure of segregation to assess the racial/ethnic population distribution. The results of the clustering statistic, and the associated significance values were then compared to rurality and interaction using the Chi-Square test to determine if hot or cold areas of access are independent of rurality and racial/ethnic spatial distributions. Lastly, the percentage of buprenorphine providers at capacity by census tract was calculated using the binary ‘at-capacity’ data attribute associated with each SAMHSA buprenorphine provider record. The results demonstrate distinct spatial variability of MOUD resources based on urbanicity and racial makeup that have significant implications for intervention or policy reform that seeks to encourage equal access to both treatment modalities.

An Examination of the Complex Pharmacological Properties of the Non-Selective Opioid Modulator Buprenorphine.

The goal of this review is to provide a recent examination of the pharmacodynamics as well as pharmacokinetics, misuse potential, toxicology, and prenatal consequences of buprenorphine. Buprenorphine is currently a Schedule III opioid in the US used for opioid-use disorder (OUD) and as an analgesic. Buprenorphine has high affinity for the mu-opioid receptor (MOR), delta (DOR), and kappa (KOR) and intermediate affinity for the nociceptin (NOR). Buprenorphine's active metabolite, norbuprenorphine, crosses the blood-brain barrier, is a potent metabolite that attenuates the analgesic effects of buprenorphine due to binding to NOR, and is responsible for the respiratory depressant effects. The area under the concentration curves are very similar for buprenorphine and norbuprenorphine, which indicates that it is important to consider this metabolite. Crowding sourcing has identified a buprenorphine street value (USD 3.95/mg), indicating some non-medical use. There have also been eleven-thousand reports involving buprenorphine and minors (age < 19) at US poison control centers. Prenatal exposure to clinically relevant dosages in rats produces reductions in myelin and increases in depression-like behavior. In conclusion, the pharmacology of this OUD pharmacotherapy including the consequences of prenatal buprenorphine exposure in humans and experimental animals should continue to be carefully evaluated.

Effects of selective dopamine D3 receptor partial agonist/antagonists on oxycodone self-administration and antinociception in monkeys.

Recent studies suggest that dopamine D3 receptors (D3R) may be a therapeutic target for opioid use disorders (OUD). This study examined the effects of the D3Rpartial agonist (±)VK4-40 and the D3R-selective antagonist (±)VK4-116, compared to the mu-opioid receptor antagonist naltrexone (NTX), in nonhuman primate models of OUD and antinociception. Adult male and female (N = 4/sex) cynomolgus monkeys were trained to self-administer oxycodone (0.003-0.1 mg/kg/injection) first under a fixed-ratio (FR) and then a progressive-ratio (PR) schedule of reinforcement during daily 1- and 4-hr sessions, respectively. Under the FR schedule, intravenous NTX (0.01-0.1 mg/kg), (±)VK4-116 (1.0-10 mg/kg), and (±)VK4-40 (1.0-10 mg/kg) were studied in combination with the peak oxycodone dose and a dose on the descending limb of the dose-effect curve; NTX and (±)VK4-40 were also studied at the peak of the PR dose-response curve (N = 4). Following saline extinction, each compound was examined on oxycodone-induced reinstatement. Finally, these compounds were assessed in adult male rhesus monkeys (N = 3) in a warm-water (38 °C, 50 °C, 54 °C) tail withdrawal assay. NTX decreased responding on the peak of the FR oxycodone dose-response curve, but increased responding on the descending limb. (±)VK4-40, but not (±)VK4-116, significantly decreased peak oxycodone self-administration; (±)VK4-40 did not increase responding on the descending limb. NTX and (±)VK4-40, but not (±)VK4-116, attenuated oxycodone-induced reinstatement. Under PR responding, NTX and (±)VK4-40 decreased breakpoints. Oxycodone-induced antinociception was attenuated by NTX, but not by (±)VK4-40 or (±)VK4-116. Together, these results suggest that further research evaluating the effects of (±)VK4-40 as a novel pharmacotherapy for OUD is warranted.

Suvorexant, an FDA-approved dual orexin receptor antagonist, reduces oxycodone self-administration and conditioned reinstatement in male and female rats.

Background: The Department of Health and Human Services reports that prescription pain reliever (e.g., oxycodone) misuse was initiated by 4,400 Americans each day in 2019. Amid the opioid crisis, effective strategies to prevent and treat prescription opioid use disorder (OUD) are pressing. In preclinical models, the orexin system is recruited by drugs of abuse, and blockade of orexin receptors (OX receptors) prevents drug-seeking behavior. The present study sought to determine whether repurposing suvorexant (SUV), a dual OX receptor antagonist marketed for the treatment of insomnia, can treat two features of prescription OUD: exaggerated consumption and relapse. Methods: Male and female Wistar rats were trained to self-administer oxycodone (0.15mg/kg, i. v., 8h/day) in the presence of a contextual/discriminative stimulus (SD) and the ability of SUV (0-20mg/kg, p. o.) to decrease oxycodone self-administration was tested. After self-administration testing, the rats underwent extinction training, after which we tested the ability of SUV (0 and 20mg/kg, p. o.) to prevent reinstatement of oxycodone seeking elicited by the SD. Results: The rats acquired oxycodone self-administration and intake was correlated with the signs of physical opioid withdrawal. Additionally, females self-administered approximately twice as much oxycodone as males. Although SUV had no overall effect on oxycodone self-administration, scrutiny of the 8-h time-course revealed that 20mg/kg SUV decreased oxycodone self-administration during the first hour in males and females. The oxycodone SD elicited strong reinstatement of oxycodone-seeking behavior that was significantly more robust in females. Suvorexant blocked oxycodone seeking in males and reduced it in females. Conclusions: These results support the targeting of OX receptors for the treatment for prescription OUD and repurposing SUV as pharmacotherapy for OUD.

Practical Pharmacotherapy for Opioid Use Disorder in the Age of Fentanyl

AbstractOpioid use disorder (OUD) is a serious public health threat. Pharmacotherapy, commonly known as medications for opioid use disorder (MOUD), is established as the cornerstone of OUD treatment. MOUDs reduce likelihood of relapse, promote recovery, and save lives. However, many clinicians are still reluctant to use these medications, in part due to inadequate training and experience. In light of the ongoing opioid overdose epidemic, it has become ever more important for clinicians to confidently and thoughtfully deploy these medications to help patients struggling with OUD. To aid busy clinicians, we have put together a review of the extant literature on three FDA-approved pharmacotherapy options—methadone, buprenorphine, and extended-release naltrexone—with a heavy focus on practical clinical application. We discuss how to effectively engage patients with OUD and initiate them on MOUDs—especially when their primary misused drug is fentanyl. We also review novel strategies, such as buprenorphine microinduction, as well as suggested best practice to effectively transition between MOUDs. Finally, we synthesize our review and recommendations in an algorithmic flowchart to provide visually compelling information.FundingNo Funding

Surmounting Withdrawal to Initiate Fast Treatment with Naltrexone (SWIFT): A stepped wedge hybrid type 1 effectiveness-implementation study

BackgroundExtended-release injectable naltrexone (XR-NTX) is an effective treatment for opioid use disorder (OUD), but initiation remains a barrier to implementation. Standard practice requires a 10- to 15-day inpatient admission prior to XR-NTX initiation and involves a methadone or buprenorphine taper followed by a 7- to 10-day washout, as recommended in the Prescribing Information for XR-NTX. A 5- to 7-day rapid induction approach was developed that utilizes low-dose oral naltrexone and non-opioid medications. MethodsThe CTN-0097 Surmounting Withdrawal to Initiate Fast Treatment with Naltrexone (SWIFT) study was a hybrid type I effectiveness-implementation trial that compared the effectiveness of the standard procedure (SP) to the rapid procedure (RP) for XR-NTX initiation across six community inpatient addiction treatment units, and evaluated the implementation process. Sites were randomized to RP every 14 weeks in an optimized stepped wedge design. Participants (target recruitment = 450) received the procedure (SP or RP) that the site was implementing at time of admission. The hypothesis was RP will be non-inferior to SP on proportion of inpatients who receive XR-NTX, with a shorter admission time for RP. Superiority testing of RP was planned if the null hypothesis of inferiority of RP to SP was rejected. DiscussionIf RP for XR-NTX initiation is shown to be effective, the shorter inpatient stay could make XR-NTX more feasible and have an important public health impact expanding access to OUD pharmacotherapy. Further, a better understanding of facilitators and barriers to RP implementation can help with future translatability and uptake to other community programs.Trial Registration: NCT 04762537 Registered February 21, 2021.

Racial inequities in opioid use disorder management: can the anesthesiologist improve outcomes?

Racial inequities in opioid use disorder management: can the anesthesiologist improve outcomes?

Continued Posttrial Benefits of Buprenorphine Extended Release: RECOVER Study Findings.

This analysis describes participants' opioid use disorder (OUD) outcomes for 18 months after discontinuing extended-release buprenorphine injection (BUP-XR, SUBLOCADE). The RECOVER (Remission From Chronic Opioid Use: Studying Environmental and Socioeconomic Factors on Recovery) study recruited participants from BUP-XR clinical trials (NCT02357901, NCT025100142, and NCT02896296) to assess whether there were sustained benefits after leaving the trial. Abstinence from opioids and from all illicit substances (excluding medical cannabis), health-related quality of life, depression, and employment were measured after BUP-XR discontinuation and change in outcomes assessed at 6, 12, and 18 months. Results were analyzed within the full cohort and by duration of BUP-XR treatment (0-2 months, 3-5 months, 6-11 months, 12 months, or 13-18 months) with and without inverse probability weights adjusting for differences in baseline characteristics. Of 533 participants, 529 were assessed over the 18-month study period. Further posttrial pharmacotherapy was reported by 33% of participants. At RECOVER baseline, longer BUP-XR was associated with higher abstinence (0-2 months BUP-XR [n = 116]: 38.8%; 3-5 months BUP-XR [n = 61]: 41.0%; 6-11 months BUP-XR [n = 86]: 68.6%; 12 months BUP-XR [n = 135]: 71.9%; 18 months BUP-XR [n = 131]: 88.2%) and greater 12-Item Short Form Health Survey mental component scores. Over 60% of participants had stable or improved outcomes at 6, 12, and 18 months assessments. Overall 47% of participants self-reported sustained opioid abstinence for the full 18-month follow-up, with greater sustained abstinence associated with longer BUP-XR treatment duration. A sensitivity analysis, removing patients receiving medications for OUD, yielded similar results. Participants from BUP-XR clinical trials who continued into RECOVER maintained or improved on numerous outcomes over 18 months, demonstrating the long-term positive impact of OUD pharmacotherapy.

Extended-release pharmacotherapy for opioid use disorder (EXPO): protocol for an open-label randomised controlled trial of the effectiveness and cost-effectiveness of injectable buprenorphine versus sublingual tablet buprenorphine and oral liquid methadone

BackgroundSublingual tablet buprenorphine (BUP-SL) and oral liquid methadone (MET) are the daily, standard-of-care (SOC) opioid agonist treatment medications for opioid use disorder (OUD). A sizable proportion of the OUD treatment population is not exposed to sufficient treatment to attain the desired clinical benefit. Two promising therapeutic technologies address this deficit: long-acting injectable buprenorphine and personalised psychosocial interventions (PSI). This study will determine (A) the effectiveness and cost-effectiveness — monthly injectable, extended-release (BUP-XR) in a head-to-head comparison with BUP-SL and MET, and (B) the effectiveness of BUP-XR with adjunctive PSI versus BUP-SL and MET with PSI. Safety, retention, craving, substance use, quality-adjusted life years, social functioning, and subjective recovery from OUD will be also evaluated.MethodsThis is a pragmatic, multi-centre, open-label, parallel-group, superiority RCT, with a qualitative (mixed-methods) evaluation. The study population is adults. The setting is five National Health Service community treatment centres in England and Scotland. At each centre, participants will be randomly allocated (1:1) to BUP-XR or SOC. At the London study co-ordinating centre, there will also be allocation of participants to BUP-XR with PSI or SOC with PSI. With 24 weeks of study treatment, the primary outcome is days of abstinence from non-medical opioids during study weeks 2–24 combined with up to 12 urine drug screen tests for opioids. For 90% power (alpha, 5%; 15% inflation for attrition), 304 participants are needed for the BUP-XR versus SOC comparison. With the same planning parameters, 300 participants are needed for the BUP-XR and PSI versus SOC and PSI comparison. Statistical and health economic analysis plans will be published before data-lock on the Open Science Framework. Findings will be reported in accordance with the Consolidated Standards of Reporting Trials and Consolidated Health Economic Evaluation Reporting Standards.DiscussionThis pragmatic randomised controlled trial is the first evaluation of injectable BUP-XR versus the SOC medications BUP-SL and MET, with personalised PSI. If there is evidence for the superiority of BUP-XR over SOC medication, study findings will have substantial implications for OUD clinical practice and treatment policy in the UK and elsewhere.Trial registrationEU Clinical Trials register 2018-004460-63.

Patient Characteristics Associated with Opioid Abstinence after Participation in a Trial of Buprenorphine versus Injectable Naltrexone

Background and Objectives: Better understanding of predictors of opioid abstinence among patients with opioid use disorder (OUD) may help to inform interventions and personalize treatment plans. This analysis examined patient characteristics associated with opioid abstinence in the X:BOT (Extended-Release Naltrexone versus Buprenorphine for Opioid Treatment) trial. Methods: This post-hoc analysis examined factors associated with past-month opioid abstinence at the 36-week follow-up visit among participants in the X:BOT study. 428 participants (75% of original sample) attended the visit at 36 weeks. Logistic regression models were used to estimate the probability of opioid abstinence across various baseline sociodemographics, clinical characteristics, and treatment variables. Results: Of the 428 participants, 143 (33%) reported abstinence from non-prescribed opioids at the 36-week follow-up. Participants were more likely to be opioid abstinent if randomized to XR-NTX (compared to BUP-NX), were on XR-NTX at week 36 (compared to those off OUD pharmacotherapy), successfully inducted onto either study medication, had longer time on study medication, reported a greater number of abstinent weeks, or had longer time to relapse during the 24-week treatment trial. Participants were less likely to be abstinent if Hispanic, had a severe baseline Hamilton Depression Rating (HAM-D) score, or had baseline sedative use. Conclusions: A substantial proportion of participants was available at follow-up (75%), was on OUD pharmacotherapy (53%), and reported past-month opioid abstinence (33%) at 36 weeks. A minority of patients off medication for OUD reported abstinence and additional research is needed exploring patient characteristics that may be associated with successful treatment outcomes.

A randomized clinical trial of strengths-based case management to link emergency department patients to opioid use disorder treatment

BackgroundDespite the existence of effective pharmacotherapies, rates of opioid use disorder and opioid overdose deaths have continued to increase. Emergency department (ED) visits provide an important opportunity to engage in treatment patients with untreated opioid use disorder (OUD). Case management implemented in other settings is effective in linking those with opioid and other drug use disorders to longer-term treatment, but research has not established its efficacy in the ED. Here we report the results of a trial of Strengths-Based Case Management (SBCM) for people with untreated OUD who are identified during ED visits, with the primary goal of linking them to pharmacologic treatment. MethodsThe study identified patients with untreated OUD during a treatment episode at a large urban ED. The study randomly assigned three hundred participants in 1:1 ratio to receive SBCM or screening, assessment, and referral (SAR) to OUD treatment. Those assigned to SBCM received up to six sessions of SBCM with the primary goal of linkage to treatment. Primary outcomes were initiation of treatment and engagement in pharmacotherapy for OUD. The study defined a “successful outcome” for opioid use as a 3-month urine negative for illicit opioids and no more than 2 days of self-reported opioid misuse in the 4 weeks prior to the 3-month interview. ResultsRates of treatment initiation were not significantly different in the SBCM and SAR groups (57.4% vs. 49.7%, respectively, p > 0.05), nor did engagement in pharmacotherapy differ significantly between groups (p > 0.05). During the 90 days following the index ED visit, SBCM and SAR participants engaged in pharmacotherapy for a mean of 21.8% (SD = 35.1%) versus 17.7% (SD = 31.0%) of days, respectively. Likewise, no significant difference occurred between groups in rates of “successful opioid use outcome” as defined a priori (p > 0.05), although self-reported opioid use over the entire 6-month follow-up period was lower in the SBCM group (10.8 vs. 13.4 days/month, p = 0.042). ConclusionsSBCM-ED did not improve OUD treatment initiation and engagement in this ED study. Although these findings do not necessarily generalize to all EDs, other approaches, such as direct referral or initiation of treatment in the ED, have considerable empirical support, and should be implemented where they are feasible.

Association of Adverse Events in Opioid Addiction Treatment With Quality Measure for Continuity of Pharmacotherapy.

Several quality measures for continuity of substance use care are being used in accountability programs, but it is not known whether they are predictive of better patient outcomes. We analyzed whether opioid use disorder (OUD) patients in the care of clinicians and practices with higher rates on one of these measures-continuity of pharmacotherapy for OUD-have a lower risk of overdose and detox events using Medicare data. For a 10-percentage point increase in an individual clinician's measure rate, the estimated odds ratios of a patient experiencing each of these two events were 0.92 (95% confidence interval [CI] 0.85 to 0.99) for overdose and 0.83 (95% CI 0.75 to 0.92) for detox. The corresponding estimates at the practice level were 0.90 (95% CI 0.85 to 0.95) for overdose and 0.83 (95% CI 0.77 to 0.89) for detox. These results suggest that a clinician's or practice's higher measure rate for continuity of pharmacotherapy for OUD is predictive of their patients' lower likelihood of having an adverse event. The findings contribute to a growing body of evidence on the importance of treatment continuity for OUD and support the validity of measuring continuity in provider-level accountability programs.

Sex-Specific Risk Factors and Health Disparity Among Hepatitis C Positive Patients Receiving Pharmacotherapy for Opioid Use Disorder: Findings From a Propensity Matched Analysis.

The incidence of opioid-related fatality has reached unparalleled levels across North America. Patients with comorbid hepatitis C virus (HCV) remain the most vulnerable and difficult to treat. Considering the unique challenges associated with this population, we aimed to re-examine the impact of HCV on response to medication assistant treatment for opioid use disorder and establish sex-specific risk factors affecting care. This study employs a multi-center prospective cohort design, with 1-year follow-up. Patients aged ≥18, receiving methadone for opioid use disorder were recruited from a network of outpatient opioid addiction treatment centers across Southern Ontario, Canada. Patients with ≥50% positive opioid urine screens over 1 year of follow-up were classified as poor responders. The prognostic impact of HCV on response was established using a propensity score matched analysis. Sex-specific regression models were constructed to evaluate risk factors for treatment response. Among participants eligible for inclusion (n = 1234), HCV was prevalent in 25% (n = 307). HCV patients exhibited significantly higher rates of high-risk opioid consumption patterns 35.29% (standard deviation 0.478). Sex-specific examination revealed females with HCV incur a 2 times increased risk for high-risk opioid consumption behaviors (female odds ratio: 1.95, 95% confidence interval 1.23, 3.10; P = 0.01). Findings from this study establish the link between HCV and poor treatment response, with differentially higher risk among female patients. In light of the high potential for overdose among this population, concerted efforts are required for distinguishing the source for sex-based disparities, in addition to establishing trauma and gender informed treatment protocols.

Factors Associated With Initial Treatment Choice, Engagement, and Discontinuation for Patients With Opioid Use Disorder.

Pharmacotherapy for opioid use disorder is effective but underused from a clinical perspective, and average treatment duration is shorter than current recommendations. In this analysis, the authors examined factors associated with initiation of, engagement in, and duration of treatment among patients with opioid use disorder. Using the OptumLabs Data Warehouse (a large, national, deidentified database of commercial or Medicare Advantage plan enrollees), the authors identified a sample of 204,225 patients with opioid use disorder between July 1, 2010, and April 1, 2019. Factors associated with initial treatment type were identified with multinomial logistic regression. The odds of treatment engagement, defined as two claims for treatment and a treatment episode of ≥30 days, were estimated with logistic regression. The hazard ratios for treatment discontinuation were estimated with a Cox proportional hazards model. Treatment initiation with pharmacotherapy (alone or in combination with psychosocial therapy) was associated with higher odds of treatment engagement and a lower hazard of treatment discontinuation. Patients with certain behavioral health conditions (e.g., anxiety or mood disorders) had higher odds of initiating treatment with pharmacotherapy and engaging in treatment and a lower hazard of discontinuing treatment. Patients with certain painful general health conditions (e.g., fibromyalgia or musculoskeletal disorders) had lower odds of initiating and engaging in treatment. Treatment initiation with pharmacotherapy was associated with treatment engagement and duration. Previous contact with behavioral health treatment may support initiating, engaging in, and remaining in treatment. Patients with painful conditions may benefit from provider support in initiating treatment for opioid use disorder.

Psychiatric comorbidity and treatment outcomes in patients with opioid use disorder: Results from a multisite trial of buprenorphine-naloxone and methadone

BackgroundIndividuals treated for opioid use disorder (OUD) have high rates of psychiatric disorders potentially diminishing treatment outcomes. We examined long-term treatment experiences and outcomes by type of psychiatric disorder among participants who participated in the Starting Treatment with Agonist Replacement Therapies (START) study and its follow-up study. MethodsWe categorized the 593 participants who completed the Mini-International Neuropsychiatric Interview (MINI) during the START follow-up study into four mutually exclusive groups to indicate current psychiatric diagnosis: 1) bipolar disorder (BPD; n = 51), 2) major depressive disorder (MDD; n = 85), 3) anxiety disorder (AXD; n = 121), and 4) no comorbid mental disorder (NMD; n = 336). We compared participants’ baseline characteristics and treatment outcomes. ResultsGroups with mental disorders had worse substance use outcomes and poorer psychosocial functioning than the NMD group. Participants with BPD had significantly more self-reported days using opioids (Mean: 8.6 for BPD vs. 3.4 days for NMD, p < 0.01) and heroin (Mean: 6.4 for BPD vs. 2.0 for MDD, 3.1 days for NMD, p < 0.05) in the 30 days prior to the final interview. Compared to patients without mental disorders, patients with MDD spent more time engaged with OUD pharmacotherapy during the ∼16-month period between MINI and final interview (mean: 71.6 % vs. 50.6 %; p < 0.001). ConclusionsOur results show that treatment outcomes in individuals with OUD vary by psychiatric comorbidity groups, which supports the need for mental health assessment and treatment for psychiatric conditions in the context of pharmacotherapy for patients with OUD.

A Novel Maintenance Therapeutic for Opioid Use Disorder.

Opioid use disorder (OUD) is a major socioeconomic burden. An ideal OUD pharmacotherapy will mitigate the suffering associated with opioid-withdrawal, inhibit the effects of high efficacy opioids, and minimize opioid-cravings while being safe and accessible to a diverse patient population. Although current OUD pharmacotherapies inhibit the euphoric effects of opioids of abuse, the extent to which they safely alleviate withdrawal and opioid-cravings corresponds with their intrinsic µ opioid receptor (MOR) efficacy. In addition to inhibiting the euphoric effects of opioids of abuse, the medium efficacy MOR agonist buprenorphine alleviates withdrawal and opioid-cravings, but its intrinsic MOR efficacy is sufficient such that its utility is limited by abuse and safety liabilities. Although the MOR antagonist naltrexone minimizes euphoria and has no abuse liability, it exacerbates suffering associated with withdrawal and opioid cravings. Therefore, a therapeutic with intrinsic MOR activity between the partial agonist (buprenorphine) and the antagonist (naltrexone) would strike a balance between the benefits and liabilities of these two therapeutics. To address this need, we derived RM1490, an MOR agonist based on a nonmorphinan scaffold that exhibits approximately half the intrinsic MOR efficacy of buprenorphine. In a series of preclinical assays, we compared RM1490 with buprenorphine and naltrexone at doses that achieve therapeutic levels of central nervous system MOR occupancy. RM1490 exhibited a behavioral profile consistent with reduced reward, dependence, and precipitated withdrawal liabilities. RM1490 was also more effective than buprenorphine at reversing the respiratory depressant effects of fentanyl and did not suppress respiration when combined with diazepam. SIGNIFICANCE STATEMENT: In preclinical studies, RM1490 has a physiological and behavioral profile suitable for opioid use disorder maintenance therapy.

Switching pharmacies leads to gaps in medication possession in individuals treated with buprenorphine

BackgroundNot all pharmacies stock and dispense buprenorphine, potentially complicating continuous access to care for patients with opioid use disorder (OUD). This may become problematic if a patient’s primary pharmacy can no longer provide buprenorphine, and the patient cannot locate a new pharmacy. ObjectivesTo identify how often patients treated with buprenorphine for OUD switch pharmacies and to estimate the association between switching pharmacies and a clinically significant gap in therapy of 7 days or longer. MethodsA retrospective repeated measures longitudinal cohort design was used. Patients initiating treatment with a buprenorphine product indicated for OUD were identified from the 2016-2018 Texas Prescription Monitoring Program. The predictor of interest—switching pharmacies—was defined by comparing the dispensaries used between subsequent prescriptions. The outcome of interest was defined as a gap in medication possession of 7 days or longer on the basis of the National Quality Forum’s definition of continuity of pharmacotherapy for OUD. A generalized estimating equation approach was used to estimate a repeated measures logistic regression measuring the association between switching pharmacies and a gap in therapy. ResultsOf 13,375 eligible patients, 29.6% switched pharmacies at least once during treatment, and 51.6% of these did so more than once. The median time to initial switch was 30 days (interquartile range: 13-66 days). When patients switched pharmacies, they were significantly more likely to have a gap in therapy of between 7 and 29 days (adjusted odds ratio 1.67 [95% CI 1.57–1.78]). ConclusionPatients receiving buprenorphine switch pharmacies early and frequently in treatment, which leads to clinically significant gaps in therapy. Although qualitative explanatory work is needed to understand why patients switch pharmacies so often, pharmacists and prescribers must ensure that patients have reliable access to a convenient source of buprenorphine to prevent gaps in therapy.

Neural bases for attenuation of morphine withdrawal by Heantos-4: role of l-tetrahydropalmatine

Severe withdrawal symptoms triggered by cessation of long-term opioid use deter many individuals from seeking treatment. Opioid substitution and α2-adrenergic agonists are the current standard of pharmacotherapy for opioid use disorder in western medicine; however, each is associated with significant complications. Heantos-4 is a non-opioid botanical formulation used to facilitate opioid detoxification in Vietnam. While ongoing clinical use continues to validate its safety and effectiveness, a mechanism of action accounting for these promising effects remains to be specified. Here, we assess the effects of Heantos-4 in a rat model of morphine-dependence and present evidence that alleviation of naloxone-precipitated somatic withdrawal signs is related to an upregulation of mesolimbic dopamine activity and a consequent reversal of a hypodopaminergic state in the nucleus accumbens, a brain region implicated in opioid withdrawal. A central dopaminergic mechanism is further supported by the identification of l-tetrahydropalmatine as a key active ingredient in Heantos-4, which crosses the blood–brain barrier and shows a therapeutic efficacy comparable to its parent formulation in attenuating withdrawal signs. The anti-hypodopaminergic effects of l-tetrahydropalmatine may be related to antagonism of the dopamine autoreceptor, thus constituting a plausible mechanism contributing to the effectiveness of Heantos-4 in facilitating opioid detoxification.

What aspects of their child's primary care do mothers value? A qualitative analysis of perspectives of women in treatment for opioid use disorder

Preventive paediatric healthcare is essential for infant and child health. Current research, however, suggests that the delivery of routine well child care (WCC) for children affected by maternal opioid use disorder (OUD) could be improved. How mothers perceive interactions with healthcare providers may help identify ways to modify the experience of WCC, which could ultimately improve healthcare utilization, patient satisfaction and clinical outcomes. The objective of this qualitative study was to assess perceptions of WCC among mothers in treatment for OUD. Four focus group sessions of 4-8 participants each (N = 22) were conducted. All study participants were receiving comprehensive behavioural and physical health support and care plus pharmacotherapy for OUD from a single outpatient treatment centre. Focus groups were semi-structured, with a standardized set of open-ended questions and follow-up prompts to engage participants in a fluid discussion. Participants were asked to identify and discuss important aspects of their youngest child's WCC and what they liked and disliked about their child's WCC. Grounded theory analysis was used to identify themes. Several aspects of WCC were identified as important to the mothers. Main themes identified included (1) mother-provider relationship, (2) communication with healthcare team and (3) support for mother's OUD treatment. Participants discussed their desire to be heard and understood and wanted the entire healthcare team and clinic staff to see them as mothers first and foremost, not merely as individuals with OUD. Future attempts to refine care may consider healthcare models that highlight open communication and personalized care and offer strong support and ongoing encouragement for the mother's OUD treatment and recovery process.