Sublingual Buprenorphine-naloxone Research Articles

Extended-Release Injection vs Sublingual Buprenorphine for Opioid Use Disorder With Fentanyl Use

Fentanyl has exacerbated the opioid use disorder (OUD) and opioid overdose epidemic. Data on the effectiveness of medications for OUD among patients using fentanyl are limited. To assess the effectiveness of sublingual or extended-release injection formulations of buprenorphine for the treatment of OUD among patients with and without fentanyl use. Post hoc analysis of a 24-week, randomized, double-blind clinical trial conducted at 35 outpatient sites in the US from December 2015 to November 2016 of sublingual buprenorphine-naloxone vs extended-release subcutaneous injection buprenorphine (CAM2038) for patients with OUD subgrouped by presence vs absence of fentanyl or norfentanyl in urine at baseline. Study visits with urine testing occurred weekly for 12 weeks, then 6 times between weeks 13 and 24. Data were analyzed on an intention-to-treat basis from March 2022 to August 2023. Weekly and monthly subcutaneous buprenorphine vs daily sublingual buprenorphine-naloxone. Retention in treatment, percentage of urine samples negative for any opioids (missing values imputed as positive), percentage of urine samples negative for fentanyl or norfentanyl (missing values not imputed), and scores on opiate withdrawal scales and visual analog craving scales. Of 428 participants, 123 (subcutaneous buprenorphine, n = 64; sublingual buprenorphine-naloxone, n = 59; mean [SD] age, 39.1 [10.8] years; 75 men [61.0%]) had evidence of baseline fentanyl use and 305 (subcutaneous buprenorphine, n = 149; buprenorphine-naloxone, n = 156; mean [SD] age, 38.1 [11.1] years; 188 men [61.6%]) did not have evidence of baseline fentanyl use. Study completion was similar between the fentanyl-positive (60.2% [74 of 123]) and fentanyl-negative (56.7% [173 of 305]) subgroups. The mean percentage of urine samples negative for any opioid were 28.5% among those receiving subcutaneous buprenorphine and 18.8% among those receiving buprenorphine-naloxone in the fentanyl-positive subgroup (difference, 9.6%; 95% CI, -3.0% to 22.3%) and 36.7% among those receiving subcutaneous buprenorphine and 30.6% among those receiving buprenorphine-naloxone in the fentanyl-negative subgroup (difference, 6.1%; 95% CI, -1.9% to 14.1%), with significant main associations of baseline fentanyl status and treatment group. In the fentanyl-positive subgroup, the mean percentage of urine samples negative for fentanyl during the study was 74.6% among those receiving subcutaneous buprenorphine vs 61.9% among those receiving sublingual buprenorphine-naloxone (difference, 12.7%; 95% CI, 9.6%-15.9%). Opioid withdrawal and craving scores decreased rapidly after treatment initiation across all groups. In this post hoc analysis of a randomized clinical trial of sublingual vs extended-release injection buprenorphine for OUD, buprenorphine appeared to be effective among patients with baseline fentanyl use. Patients with fentanyl use had fewer opioid-negative urine samples during the trial compared with the fentanyl-negative subgroup. These findings suggest that the subcutaneous buprenorphine formulation may be more effective at reducing fentanyl use. ClinicalTrials.gov Identifier: NCT02651584.

Buprenorphine deaths confirmed by toxicology reveal a low proportion of opioid agonist treatment before death in Finland.

We studied opioid agonist treatment (OAT) status before buprenorphine-related death in Finland, where buprenorphine is the principal OAT medicine and also the most misused opioid, through a retrospective population-based study using medico-legal cause-of-death investigation and OAT patient records. The study included all death cases (N = 570) between 2018 and 2020 with a buprenorphine or norbuprenorphine finding in post-mortem toxicology and with known drug misuse history or concomitant findings of illicit drugs. Of the deceased, 10% had received OAT in the year before death. Less than 1% of individuals < 25 years had received OAT, whereas the proportion in individuals ≥ 25 years was 13% (p < 0.001). There were significantly more females and more fatal poisonings (p < 0.001) among those < 25 years than among those ≥ 25 years. OAT medication at the time of death was sublingual buprenorphine-naloxone in 74% and subcutaneous buprenorphine in 23%. Except for significantly fewer benzodiazepine findings among those receiving OAT, minimal differences were found in terms of age, gender, cause and manner of death, or concomitant substance use between the deceased in and outside of OAT. Concomitant misuse of benzodiazepines, psychostimulants, alcohol, and gabapentinoids was frequent both in and outside of OAT and likely contributed to the death. These results suggest that access to OAT especially for young people and treatment of multiple addictions should be improved. Comprehensive information from medico-legal cause-of-death investigation as a starting point, combined with subsequent ante-mortem patient records, proved to be a successful approach to shed light on the Finnish scene of buprenorphine mortality.

Machine Learning-Driven Analysis of Individualized Treatment Effects Comparing Buprenorphine and Naltrexone in Opioid Use Disorder Relapse Prevention.

A trial comparing extended-release naltrexone and sublingual buprenorphine-naloxone demonstrated higher relapse rates in individuals randomized to extended-release naltrexone. The effectiveness of treatment might vary based on patient characteristics. We hypothesized that causal machine learning would identify individualized treatment effects for each medication. This is a secondary analysis of a multicenter randomized trial that compared the effectiveness of extended-release naltrexone versus buprenorphine-naloxone for preventing relapse of opioid misuse. Three machine learning models were derived using all trial participants with 50% randomly selected for training (n = 285) and the remaining 50% for validation. Individualized treatment effect was measured by the Qini value and c-for-benefit, with the absence of relapse denoting treatment success. Patients were grouped into quartiles by predicted individualized treatment effect to examine differences in characteristics and the observed treatment effects. The best-performing model had a Qini value of 4.45 (95% confidence interval, 1.02-7.83) and a c-for-benefit of 0.63 (95% confidence interval, 0.53-0.68). The quartile most likely to benefit from buprenorphine-naloxone had a 35% absolute benefit from this treatment, and at study entry, they had a high median opioid withdrawal score (P < 0.001), used cocaine on more days over the prior 30 days than other quartiles (P < 0.001), and had highest proportions with alcohol and cocaine use disorder (P ≤ 0.02). Quartile 4 individuals were predicted to be most likely to benefit from extended-release naltrexone, with the greatest proportion having heroin drug preference (P = 0.02) and all experiencing homelessness (P < 0.001). Causal machine learning identified differing individualized treatment effects between medications based on characteristics associated with preventing relapse.

The sociodemographic profile and the challenges associated with treatment and rehabilitation in female heroin users: A case series from Northeast India.

Females with opioid use disorder (OUD) rarely seek help for addiction. We present a series of seven females with OUD attending a tertiary care addiction treatment setting in Assam between December 2022 to August 2023. Most of the patients were primary-educated, young adults, housewives, from lower to middle socioeconomic strata, and were residents of rural or semi-urban areas. All were married, and around half of them were separated. All the patients were dependent on heroin and tobacco. Five of them initiated heroin use while modeling their spouse. Three patients were injecting heroin, and one was seropositive with both HCV and HIV. Five patients received sublingual buprenorphine-naloxone, and three of them followed up subsequently. Financial difficulty, poor family support, and intimate partner violence were major challenges for treatment-seeking and regular follow-up. This case series highlights the need for systematic study and gender-responsive care of females with OUD in Assam.

Evaluation of opioid use disorder treatment outcomes in patients receiving split daily versus once daily dosing of buprenorphine-naloxone

IntroductionIn clinical practice, sublingual (SL) buprenorphine-naloxone is prescribed as once daily or split daily dosing for the management of opioid use disorder (OUD). Evidence is lacking that assesses how split daily buprenorphine-naloxone affects OUD outcomes. This study aims to evaluate how the dosing frequency of SL buprenorphine-naloxone impacts therapy effectiveness when treating patients with OUD. MethodsThis retrospective analysis included adult outpatients prescribed treatment with SL buprenorphine-naloxone for OUD between July 1, 2016, and March 1, 2020. The study excluded patients with sickle cell disease, recent methadone treatment, or pregnancy. We characterized study groups by dosing frequency, either once daily or split dosing. The study compared retention in treatment, medication adherence, adherence to treatment program, and hospital encounters between groups. ResultsThe study screened eight-hundred and seven patients, and included 250 patients newly prescribed SL buprenorphine-naloxone. Fifty-seven patients (22.8 %) were prescribed once daily dosing and 193 patients (77.2 %) were prescribed split daily dosing. The study found no significant differences noted in 12-month rates of treatment retention (52.6 % vs. 45.6 %, p = .35). These outcomes remained similar when assessed at three and six months. Within a year of buprenorphine-naloxone initiation, the study found no differences in the percentage of patients with hospitalizations (26.3 % vs. 38.3 %, p = .10), median number of hospitalizations (2 vs. 2), or proportion of days covered by a prescription ≥80 % (93.3 % vs. 92.0 %, p = .82). ConclusionsIn this study, patients receiving once daily buprenorphine-naloxone had similar treatment outcomes to patients receiving split dosing. Further controlled studies are necessary to evaluate which patients are more likely to benefit from split dosing.

Buprenorphine-Naloxone Film Versus Tablets for Opioid Use Disorder

What Is the Issue?&#x0D; &#x0D; Medication for opioid use disorder is essential for reducing cravings, withdrawal symptoms, and facilitating recovery, with buprenorphine being preferred over methadone by health care providers and people with opioid use disorder due to its lower overdose risk and perceived lower side effect profile.&#x0D; In Canada, buprenorphine is available in various formulations, including buprenorphine-naloxone (BUP-NAL), commonly chosen for its safety benefits and convenience.&#x0D; Sublingual buprenorphine-naloxone films offer faster dissolution and potentially other benefits compared to sublingual tablets, evaluating their comparative clinical and cost-effectiveness is important as they become more widely available.&#x0D; &#x0D; What Did We Do?&#x0D; &#x0D; To inform decisions about the appropriate selection of BUP-NAL formulations for treating individuals with opioid use disorder, CADTH sought to identify and summarize literature comparing the clinical effectiveness and cost-effectiveness of sublingual BUP-NAL films versus tablets. We also attempted to identify evidence-based recommendations for the use of BUP-NAL film.&#x0D; A research information specialist conducted a literature search of the peer-reviewed and grey literature with a search strategy focused on sublingual BUP-NAL. The search was limited to English-language documents published since January 1, 2018. One reviewer screened articles for inclusion based on predefined criteria, critically appraised the included study, and narratively summarized the findings.&#x0D; &#x0D; What Did We Find?&#x0D; &#x0D; Sublingual BUP-NAL films may have lower abuse rates compared to sublingual BUP-NAL tablets among people who seek treatment at substance abuse treatment centres or who present needing medical advice or treatment for intentional misuse or abuse of potentially toxic substances, including opioids (1 study).&#x0D; We did not find any clinical effectiveness studies that assessed aspects related to drug ingestion, drug abuse cessation, treatment programs, health-related quality of life, mental health or safety of BUP-NAL films or tablets that met our criteria for this review.&#x0D; We did not find any studies on cost-effectiveness or evidence-based guidelines of sublingual BUP-NAL films or tablets that met our criteria for this review.&#x0D; &#x0D; What Does It Mean?&#x0D; &#x0D; Limited evidence from this review suggests that sublingual BUP-NAL films may lead to lower substance abuse rates compared to sublingual BUP-NAL tablets among people with OUD; however, we require more comprehensive research with rigorous methodological approaches to understand this topic better.&#x0D; Considering the low abuse potential for BUP-NAL film, decision-makers may wish to use this formulation in settings where the potential for substance abuse is high.&#x0D;

Risk of relapse to non-opioid addictive substances among opioid dependent patients treated with an opioid receptor antagonist or a partial agonist: A randomized clinical trial

Background and objectiveFirst study to assess any compensatory increase in use of non-opioid illicit substances and alcohol in opioid dependent patients randomized to treatment with extended-release naltrexone (XR-NTX) or buprenorphine-naloxone (BP-NLX) and in longer term treatment with extended-release naltrexone. MethodA multicenter, outpatient, open-label randomized clinical trial where patients received intramuscular extended-release naltrexone hydrochloride, 380 mg/month, or daily sublingual buprenorphine-naloxone 8–24/2–6 mg for 12 weeks, and an option to continue with extended-release naltrexone for an additional 36 week follow-up. The study was conducted at five urban addiction clinics and detoxification units in Norway between November 2012, and July 2016. ResultsAmong the 143 patients, 106 men and 37 women, there were no significant differences between those randomized to XR-NTX or BP-NLX in the risk of first relapse to alcohol (HR 1.31; 0.68–2.53), amphetamines (HR 0.88; 0.43–1.80), benzodiazepines (HR 1.24; 0.74–2.09) or cannabis (HR 1.55; 0.83–2.89). Also in the 36-week (12–48 weeks) follow-up period we found no significant differences between patients continuing with XR-NTX compared to those switching to XR-NTX after the randomized period in risk of first relapse to any non-opioid substance. In both study periods, the mean time in the study were longer among those relapsing to non-opioid addictive substances than those who did not. There was no significant association between first relapse to illicit opioids and first relapse to non-opioid addictive substances. ConclusionThere was no increase in the risk of relapse to non-opioid addictive substances neither in short term nor longer-term treatment with extended-release naltrexone.Trial registrationclinicaltrials.gov Identifier: NCT01717963

How I do it: weaning strategy for intrathecal drug delivery systems for chronic non-cancer pain: sublingual buprenorphine-naloxone microdosing schedule

How I do it: weaning strategy for intrathecal drug delivery systems for chronic non-cancer pain: sublingual buprenorphine-naloxone microdosing schedule

Low dose IV buprenorphine inductions for patients with opioid use disorder and concurrent pain: a retrospective case series

BackgroundHospitalizations are a vital opportunity for the initiation of life-saving opioid agonist therapy (OAT) for patients with opioid use disorder. A novel approach to OAT initiation is the use of IV buprenorphine for low dose induction, which allows patients to immediately start buprenorphine at any point in a hospitalization without stopping full agonist opioids or experiencing significant withdrawal.MethodsThis is a retrospective case series of 33 patients with opioid use disorder concurrently treated with full agonist opioids for pain who voluntarily underwent low dose induction at a tertiary academic medical center. Low dose induction is the process of initiating very low doses of buprenorphine at fixed intervals with gradual dose increases in patients who recently received or are simultaneously treated with full opioid agonists. Our study reports one primary outcome: successful completion of the low dose induction (i.e. transitioned from low dose IV buprenorphine to sublingual buprenorphine-naloxone) and three secondary outcomes: discharge from the hospital with buprenorphine-naloxone prescription, self-reported pain scores, and nursing-assessed clinical opiate withdrawal scale (COWS) scores over a 6-day period, using descriptive statistics. COWS and pain scores were obtained from day 0 (prior to starting the low dose induction) to day 5 to assess the effect on withdrawal symptoms and pain control.ResultsThirty patients completed the low dose induction (30/33, 90.9%). Thirty patients (30/33, 90.9%) were discharged with a buprenorphine prescription. Pain and COWS scores remained stable over the course of the study period. Mean COWS scores for all patients were 2.6 (SD 2.8) on day 0 and 1.6 (SD 2.6) on day 5. Mean pain scores for all patients were 4.4 (SD 2.1) on day 0 and 3.5 on day 5 (SD 2.1).ConclusionsThis study found that an IV buprenorphine low dose induction protocol was well-tolerated by a group of 33 hospitalized patients with opioid use disorder with co-occurring pain requiring full agonist opioid therapy. COWS and pain scores improved for the majority of patients. This is the first case series to report mean daily COWS and pain scores over an extended period throughout a low dose induction process.

Precipitated Opioid Withdrawal Treated With Ketamine in a Hospitalized Patient: A Case Report.

Although initiating buprenorphine in the presence of full opioid agonists has always been a clinical dilemma, the transition to primarily fentanyl in the drug supply has increased the urgency to find appropriate treatments for precipitated opioid withdrawal (POW). Although rare, lack of evidence on how to best treat POW threatens clinician and patient comfort in initiating life-saving medication for opioid use disorder. Ketamine has been used in emergency department settings to treat POW; this is the first case report of ketamine use in a hospitalized patient. A 38-year-old male patient with severe opioid use disorder presented to the emergency department with suicidality and opioid withdrawal 24 hours after last fentanyl use. In the first 24 hours of admission, he received sublingual buprenorphine-naloxone (BNX) 16-4 mg, resulting in Clinical Opiate Withdrawal Scale score increasing from 13 to over 36. The patient was admitted, and addiction medicine was consulted. The patient was diagnosed with POW, started on ketamine infusion, and given additional BNX 8-2 mg. Twelve hours after the ketamine infusion, the patient's Clinical Opiate Withdrawal Scale score improved to 18 but remained elevated. He received a second ketamine infusion plus additional BNX with complete resolution of symptoms within 8 hours, and he was stabilized and discharged on BNX 24-6 mg daily. Ketamine is a promising treatment for POW due to its potentiation of μ-opioid receptor-mediated signaling. This is the first case to describe POW in the inpatient hospital setting. More research is needed to establish the effectiveness and feasibility of ketamine as treatment for POW.

Exploring patient experience and satisfaction with depot buprenorphine formulations: A mixed-methods study.

The introduction of depot buprenorphine for the treatment of opioid dependence allows for reduced dosing frequency compared with conventional treatments, such as oral methadone and sublingual buprenorphine-naloxone. Reduced dosing frequency is perceived to reduce issues such as high out-of-pocket costs, frequent attendance to pharmacies, stigmatisation and the risk of diversion for unsanctioned opioid use. This study aims to explore the experiences of patients receiving depot buprenorphine from an Australian publicly operated drug and alcohol service. Participants were recruited from the service over a 5-week period in 2021. Twenty-eight participants consented to be involved in a mixed methods quantitative verbal survey and qualitative interview process. The majority of participants reported satisfaction with depot buprenorphine across the domains of efficacy, convenience and global satisfaction. Participants perceived benefits as increased convenience, reduced stigmatisation and the inability to 'skip' daily Medication Assisted Treatment for Opioid Dependence (MATOD) doses. There were mixed experiences with the ability for depot buprenorphine to 'hold' participants throughout the dosing interval. Reduced contact and disconnection from healthcare services were reported as an issue for some participants when initiating depot buprenorphine. Patient perceptions of depot buprenorphine appear to be deeply rooted in prior experience with 'conventional' MATOD treatments. Depot buprenorphine is seen to be beneficial socially, personally, and financially by the majority of patients interviewed. The potential for disconnection from services and mixed experiences of efficacy throughout the dosing period may negatively influence patient experience.

Homelessness and Treatment Outcomes Among Black Adults With Opioid Use Disorder: A Secondary Analysis of X:BOT.

We sought to identify the sociodemographic and clinical characteristics associated with homelessnesss, and explore the relationship between homelessnesss and treatment outcomes among Black individuals. This is a secondary analysis of the subgroup of Black participants (n = 73) enrolled in "X:BOT," a 24-week multisite randomized clinical trial comparing the effectiveness of extended-release naltrexone versus sublingual buprenorphine-naloxone (n = 570). Outcomes included medication initiation, return to extramedical use of opioids assessed by both self-report and urine toxicology, and engagement in medications for opioid use disorder (MOUD) treatment at 28 weeks postrandomization. Descriptive statistics were performed. Black participants were mostly unmarried and male, and about a third were aged 21-30 years. Among people experiencing homelessnesss, more were uninsured (45.5% [10/22] vs 19.6% [10/51]), unemployed (77.3% [17/22] vs 64.7% [33/51]), and reported alcohol (40.9% [9/22] vs 23.5% [12/51]) and sedative use (54.5% [12/22] vs 17.6% [9/51]) within the previous 30 days. Compared with housed Black individuals, a slightly higher proportion of Black individuals experiencing homelessnesss successfully initiated study medication (81.1% [18/22] vs 72.6% [37/51]); similar proportions returned to opioid use during the trial (68.2% [15/22] vs 68.6% [35/51]) and were engaged in MOUD at 28 weeks after trial entry (72.2% [13/18] vs 69.7% [23/33]) among participants located for follow-up. These descriptive results among Black patients participating in a trial of MOUD suggest that efficacious MOUD is possible despite homelessnesss with additional clinical supports such as those provided by a clinical trial.

Optimally Choosing Medication Type for Patients With Opioid Use Disorder.

Patients with opioid use disorder (OUD) tend to get assigned to one of 3 medications based on the treatment program to which the patient presents (e.g., opioid treatment programs tend to treat patients with methadone, while office-based practices tend to prescribe buprenorphine). It is possible that optimally matching patients with treatment type would reduce the risk of return to regular opioid use (RROU). We analyzed data from 3 comparative effectiveness trials from the US National Institute on Drug Abuse Clinical Trials Network (CTN0027, 2006-2010; CTN0030, 2006-2009; and CTN0051 2014-2017), in which patients with OUD (n= 1,459) were assigned to treatment with either injection extended-release naltrexone (XR-NTX), sublingual buprenorphine-naloxone (BUP-NX), or oral methadone. We learned an individualized rule by which to assign medication type such that risk of RROU during 12 weeks of treatment would be minimized, and then estimated the amount by which RROU risk could be reduced if the rule were applied. Applying our estimated treatment rule would reduce risk of RROU compared with treating everyone with methadone (relative risk (RR)= 0.79, 95% confidence interval (CI): 0.60, 0.97) or treating everyone with XR-NTX (RR= 0.71, 95% CI: 0.47, 0.96). Applying the estimated treatment rule would have resulted in a similar risk of RROU to that of with treating everyone with BUP-NX (RR= 0.92, 95% CI: 0.73, 1.11).

Depot buprenorphine as an opioid agonist therapy in New South Wales correctional centres: a costing model

BackgroundIn 2019 daily liquid methadone and sublingual buprenorphine-naloxone were primary opioid agonist treatments for correctional centres in New South Wales, Australia. However, both had significant potential for diversion to other patients, and their daily administration was resource intensive. An alternative treatment in the form of subcutaneous depot buprenorphine became a viable option following a safety trial in 2020 – the UNLOC-T study. Depot preparation demonstrated advantages over current treatments as more difficult to divert and requiring fewer administrations. This paper reports the results of economic modelling of staffing costs in medication administration comparing depot buprenorphine, methadone, and sublingual buprenorphine provision in UNLOC-T trial facilities.MethodsThe costing study adopted a micro-costing approach involving the synthesis of cost data from the UNLOC-T clinical trial as well as data collected from Justice Health and Forensic Mental Health Network records. Labour and materials data were collected during site observations and interviews. Costs were calculated from two payer perspectives: a) the New South Wales (state) government which funds custodial and health services; and b) the Australian Commonwealth government, which pays for medications. The analysis compared the monthly-per-patient cost for each of the three medications in trial-site facilities during July 2019. This was followed by simulation of depot buprenorphine implementation across the study population. Costs associated with medical assessment and reviews were excluded.ResultsThe monthly-per-patient New South Wales government service costs of depot buprenorphine, methadone and sublingual buprenorphine were: $151, $379 and $1,529 respectively while Commonwealth government medication costs were $434, $80 and $525. The implementation simulation found that service costs of depot buprenorphine declined as patients transitioned from weekly to monthly administration. Costs of treatment using the other medications increased as patient numbers decreased alongside fixed costs. At 12 months, monthly-per-patient service costs for depot buprenorphine, methadone and sublingual buprenorphine—which would be completely phased out by month 13—were $92, $530 and $2,162 respectively.ConclusionsDepot buprenorphine was consistently the least costly of the treatment options. Future modelling could allow for dynamic patient populations and downstream impacts for participants and the state health system.Trial registrationACTRN12618000942257. Registered 4 June 2018.

Adapting low-dose buprenorphine induction to meet patient needs: A pilot study

IntroductionLow-dose buprenorphine induction (LDBI) has been proposed to initiate buprenorphine in patients who are taking full opioid agonists in order to limit the risk of precipitated withdrawal. The objective of this study was to understand how real-world patient-specific adjustments in LDBI protocols impacted success rates in buprenorphine conversion. MethodsThis case series identified patients seen by the Addiction Medicine Consult Service at UPMC Presbyterian Hospital who were started on LDBI with transdermal buprenorphine followed by sublingual buprenorphine-naloxone between April 20, 2021, and July 20, 2021. The primary outcome was successful induction of sublingual buprenorphine. Characteristics of interest included total morphine milligram equivalents (MME) in the 24 hours prior to induction, MME during each day of induction, total time of induction, and final daily maintenance buprenorphine dose. ResultsOf the 21 patients included for analysis, 19 (91%) successfully completed LDBI and converted to a maintenance buprenorphine dose. Median (IQR) opioid analgesia utilization in the 24 hours prior to induction was 113 MME (63–166 MME) in the converted group and 83 MME (75–92 MME) in the group that did not convert. ConclusionsTransdermal buprenorphine patch followed by sublingual buprenorphine-naloxone resulted in a high success rate for LDBI. Patient-specific adjustments may be considered in order to effect a high success rate of conversion.

Rationale, design and methods of VA-BRAVE: a randomized comparative effectiveness trial of two formulations of buprenorphine for treatment of opioid use disorder in veterans

BackgroundTo address the US opioid epidemic, there is an urgent clinical need to provide persons with opioid use disorder (OUD) with effective medication treatments for OUD (MOUD). Formulations of sublingual buprenorphine/naloxone (SL-BUP/NLX) are considered the standard of care for OUD including within the Veterans Healthcare Administration (VHA). However, poor retention on MOUD undermines its effectiveness. Long-acting injectable monthly buprenorphine (INJ-BUP) (e.g., Sublocade®) has the potential to improve retention and therefore reduce opioid use and overdose. Designing and conducting studies for OUD pose unique challenges. The strategies and solutions to some of these considerations in designing Cooperative Studies Program (CSP) 2014, Buprenorphine for Treating Opioid Use Disorder in Veterans (VA-BRAVE), a randomized, 20-site, clinical effectiveness trial comparing INJ-BUP to SL-BUP/NLX conducted within the VHA may provide valuable guidance for others confronted with similar investigation challenges.MethodsThis 52-week, parallel group, open-label, randomized controlled trial (RCT) evaluates the comparative effectiveness of two current FDA-approved formulations of buprenorphine: (1) daily SL-BUP/NLX vs. (2) monthly (28-day) INJ-BUP for Veterans with moderate to severe OUD (n = 952). The primary outcomes are (1) retention in MOUD and (2) opioid abstinence. Secondary outcomes include measures of other drug use, psychiatric symptoms, medical outcomes including prevalence rates of HIV, hepatitis B and C as well as social outcomes (housing instability, criminal justice involvement), service utilization and cost-effectiveness. Special considerations in conducting a comparative effectiveness trial with this population and during COVID-19 pandemic were also included.DiscussionThe evaluation of the extended-release formulation of buprenorphine compared to the standard sublingual formulation in real-world VHA settings is of paramount importance in addressing the opioid epidemic. The extent to which this new treatment facilitates retention, decreases opioid use, and prevents severe sequelae of OUD has not been studied in any long-term trial to date. Positive findings in this trial could lead to widespread adoption of MOUD, and, if proven superior INJ-BUP, by clinicians throughout the VHA and beyond. This treatment has the potential to reduce opioid use among Veterans, improve medical, psychological, and social outcomes, and save lives at justifiable cost.Trial registration Registered at Clinicaltrials.gov NCT04375033

Association between dynamic dose increases of buprenorphine for treatment of opioid use disorder and risk of relapse.

Dynamic, adaptive pharmacologic treatment for opioid use disorder (OUD) has been previously recommended over static dosing to prevent relapse, and is aligned with personalized medicine. However, there has been no quantitative evidence demonstrating its advantage. Our objective was to estimate the extent to which a hypothetical intervention that increased buprenorphine dose in response to opioid use would affect risk of relapse over 24 weeks of follow-up. A secondary analysis of the buprenorphine arm of an open-label randomized controlled 24-week comparative effectiveness trial, 2014-17. Eight community addiction treatment programs in the United States. English-speaking adults with DSM-5 OUD, recruited during inpatient admission (n = 270). Participants were mainly white (65%) and male (72%). Participants were treated with daily sublingual buprenorphine-naloxone (BUP-NX), with dose based on clinical indication, determined by the provider. We examined a hypothetical intervention of increasing dose in response to opioid use. Outcome was relapse to regular opioid use during the 24 weeks of outpatient treatment, assessed in a survival framework. We estimated the relapse-free survival curves of participants under a hypothetical (i.e. counterfactual) intervention in which their BUP-NX dosage would be increased following their own subject-specific opioid use during the first 12 weeks of treatment versus a hypothetical intervention in which dose would remain constant. We estimated that increasing BUP-NX dose in response to recent opioid use would lower risk of relapse by 19.17 percentage points [95% confidence interval (CI) = -32.17, -6.18) (additive risk)] and 32% (0.68, 95% CI = 0.49, 0.86) (relative risk). The number-needed-to-treat with this intervention to prevent a single relapse is 6. In people with opioid use disorder, a hypothetical intervention that increases sublingual buprenorphine-naloxone dose in response to opioid use during the first 12 weeks of treatment appears to reduce risk of relapse over 24 weeks, compared with holding the dose constant after week 2.

The Predictive Value of Degree of Preference for Extended-Release Naltrexone for Treatment Adherence, Opioid Use, and Relapse

Background: Extended-release naltrexone (XR-NTX) is effective for illicit opioid abstinence as an opioid maintenance treatment. To improve treatment outcomes, patient’s preference for the modality of treatment is an important factor. Objectives: We aimed to test the relationship between baseline preference for XR-NTX and adherence to treatment, use of illicit opioids, and risk of relapse. Methods: In an open-label, Norwegian clinical trial participants with opioid use disorder were randomized to either monthly injections with XR-NTX or daily sublingual buprenorphine-naloxone (BP-NLX) for 12 weeks. Subsequently, participants could continue with their preferred medication in a 36-week follow-up and in a prolonged period of 104 weeks. Results: Of 153 participants who completed detoxification, 72% were men, with a mean age of 36 years. Preference levels were similar across the randomized groups, with no significant associations between preference and adherence to treatment, opioid use, or relapse. The BP-NLX group had a significantly higher risk of first relapse to opioids than the XR-NTX group for all levels of preference (p < 0.001) and a significantly higher number of days of illicit opioid use. In the follow-up period, the adherence rate was twice as high among participants with the highest preference compared to participants with the lowest preference, both among those who switched to XR-NTX and those who continued (hazard ratio 2.2; 1.2–4.0, p = 0.013). Opioid use was significantly higher among participants who switched to XR-NTX with the lowest preference than the medium (p = 0.003) or the highest (p = 0.001) preference. The risk of relapse to opioids, however, was significantly higher among XR-NTX continuing participants with the lowest (p = 0.002) or the medium (p = 0.043) preference than those with the highest preference. Conclusions: Individuals who matched with their preferred treatment used less illicit opioids than those who did not during short-term treatment. However, baseline preference for XR-NTX treatment primarily influenced longer term opioid use and treatment adherence.

Optimizing opioid use disorder treatment with naltrexone or buprenorphine

BackgroundRelapse rates during opioid use disorder (OUD) treatment remain unacceptably high. It is possible that optimally matching patients with medication type would reduce risk of relapse. Our objective was to learn a rule by which to assign type of medication for OUD to reduce risk of relapse, and to estimate the extent to which risk of relapse would be reduced if such a rule were used. MethodsThis was a secondary analysis of an open-label randomized controlled, 24-week comparative effectiveness trial of injection extended-release naltrexone (XR-NTX), delivered approximately every 28 days, or daily sublingual buprenorphine-naloxone (BUP-NX) for treating OUD, 2014–2017 (N = 570). Outcome was a binary indicator of relapse to regular opioid use during the 24 weeks of outpatient treatment. ResultsWe found that applying an estimated individualized treatment rule—i.e., a rule that assigns patients with OUD to either XR-NTX or BUP-NX based on their individual characteristics in such a way that risk of relapse is minimized—would reduce risk of relapse by 24 weeks by 12% compared to randomly assigned treatment. ConclusionsThe number-needed-to-treat with the estimated treatment rule to prevent a single relapse is 14. A simpler, alternative estimated rule in which homeless participants would be treated with XR-NTX and stably housed participants would be treated with BUP-NX performed similarly. These results provide an estimate of the amount by which a relatively simple change in clinical practice could be expected to improve prevention of OUD relapse.

Comparison of Treatment Retention of Adults With Opioid Addiction Managed With Extended-Release Buprenorphine vs Daily Sublingual Buprenorphine-Naloxone at Time of Release From Jail

Extended-release buprenorphine (XRB), a monthly injectable long-acting opioid use disorder (OUD) treatment, has not been studied for use in corrections facilities. To compare treatment retention following release from jail among adults receiving daily sublingual buprenorphine-naloxone (SLB) vs those receiving XRB. This open-label, randomized comparative effectiveness study included 52 incarcerated adults in New York City observed for 8 weeks postrelease between June 2019 and May 2020. Participants were soon-to-be-released volunteers from 1 men's and 1 women's jail facility who had OUDs already treated with SLB. Follow-up treatment was received at a primary care clinic in Manhattan. Data were analyzed between June 2020 and December 2020. XRB treatment was offered prior to release and continued monthly through 8 weeks after release. SLB participants continued to receive daily directly observed in-jail SLB administration, were provided a 7-day SLB supply at jail release, and followed up at a designated clinic (or other preferred clinics). Buprenorphine treatment retention at 8 weeks postrelease. A total of 52 participants were randomized 1:1 to XRB (26 participants) and SLB (26 participants). Participants had a mean (SD) age of 42.6 (10.0) years; 45 participants (87%) were men; and 40 (77%) primarily used heroin prior to incarceration. Most participants (30 [58%]) reported prior buprenorphine use; 18 (35%) reported active community buprenorphine treatment prior to jail admission. Twenty-one of 26 assigned to XRB received 1 or more XRB injection prior to release; 3 initiated XRB postrelease; and 2 did not receive XRB. Patients in the XRB arm had fewer jail medical visits compared with daily SLB medication administration (mean [SD] visits per day: XRB, 0.11 [0.03] vs SLB, 1.06 [0.08]). Community buprenorphine treatment retention at week 8 postrelease was 18 participants in the XRB group (69.2%) vs 9 in the SLB group (34.6%), and rates of opioid-negative urine tests were 72 of 130 tests in the XRB group (55.3%) and 50 of 130 tests in the SLB group (38.4%). There were no differences in rates of serious adverse events, no overdoses, and no deaths. XRB was acceptable among patients currently receiving SLB, and patients had fewer in-jail clinic visits and increased community buprenorphine treatment retention when compared with standard daily SLB treatment. These results support wider use and further study of XRB as correctional and reentry OUD treatment. ClinicalTrials.gov Identifier: NCT03604159.