Efficacy and safety of a monthly buprenorphine depot injection for opioid use disorder: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Haight, Barbara R.; Learned, Susan M; Laffont, Céline M.; Fudala, Paul J.; Zhao, Yue; Garofalo, A; Greenwald, Mark K.; Nadipelli, Vijay R; Ling, Walter; Heidbreder, Christian; Andersen, James; Bailey, Genie L.; Bartley, Scott Robert; Biunno, Michael J.; Boyett, Brent; Carr, Jesse M.; Cifuentes, Eduardo; Duarte-Sckell, Sandra Daniela; Dueno, Otto R.; Harrison, Boyde J.; Hassman, David; Hoffman, Kent Steven; Isacesu, Valentin; Ishaque, Saleem; Kakar, Rishi; Kampman, Kyle M.; Knapp, Richard D.; Konis, George; Kunovac, Jelena; Kwentus, Joseph A.; Levinson, L; Malhotra, Shishuka; Mehra, Vishaal; Mofsen, Ricky; Peyton, Marvin; Pujari, Gita G.; Ranjan, Rakesh; Rutrick, Daniel; Seal, Gregory; Segal, Scott; Shiwach, Rajinder; Thomas, Haydn M.; Ventre, Peter Paul; Vijapura, Amit K.; Walling, David; Wiest, Katharina

doi:10.1016/s0140-6736(18)32259-1

Cited by 204 publications

(179 citation statements)

References 24 publications

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“…However, despite high mean doses in some studies, which result in BUP plasma exposures at steadystate well over 3 ng/ml conferring a high level of opioid receptor blockade, there was still considerable use of illicit opioids in a large proportion of the patients. The continued use of illicit opioids despite high doses of BUP is also shown in the recently published studies with extended-release formulations using flexible [10] or high fixed doses of BUP [7]. Reduction in opioid cravings conferred by opioid receptor blockade might not be sufficient to stop illicit drug use in all patients and this is further supported by a recent finding of low correlation between opioid cravings and opioid use in patients treated with BUP [55].…”

Section: Discussionmentioning

confidence: 81%

“…This was demonstrated in a recent large induction study with SL BUP-NLX which reported that approximately 25% of patients withdrew from treatment during the first 15 days [49]. In addition, approximately 24% of patients withdrew during the 7-14 day SL BUP run-in period in a trial of an extended-release BUP formulation [7]. That doses of 16 mg and higher may be associated with lower drop-out during the induction phase has been shown in analyses of outcome trajectories from the START clinical trial in the US [40,50].…”

Section: Discussionmentioning

confidence: 93%

“…The randomized clinical trials were limited to those with a duration of at least 24 weeks in order to capture all the treatment phases induction, stabilization and maintenance in this chronic relapsing remitting disease generally requiring long-term therapy. Furthermore, a clinical efficacy trial duration of 24 weeks is required by regulatory agencies for approval of new medications for treatment of OUD [7,10]. The clinical trials selected were also limited to those conducted in Europe and North America.…”

Section: Methodsmentioning

confidence: 99%

“…The ability of BUP to block the effect of full opioid agonists on the lOR has been shown in pharmacological 'blockade' or 'challenge' studies where patients are first administered BUP at different doses and then challenged with drugs such as heroin or hydromorphone [4]. There are some authors of scientific publications claiming that an adequate opioid blockade requires an 'optimal exposure' with BUP plasma concentrations of 2-3 ng/ mL and that this is achieved with a daily sublingual (SL) dose of BUP or buprenorphine/naloxone (BUP-NLX) of 16 mg and higher [5][6][7]. However, others suggest that further research is needed to understand dose-response relationships in patients with this complex disorder [8,9].…”

Section: Introductionmentioning

confidence: 99%

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Optimal dose of buprenorphine in opioid use disorder treatment: a review of pharmacodynamic and efficacy data

Hjelmström¹,

Nordbeck²,

Tiberg³

2020

Drug Development and Industrial Pharmacy

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Context: There is currently no consensus regarding optimal dose or dose-range of buprenorphine (BUP) for treatment of opioid use disorder (OUD). Objective: To elucidate the relationship between BUP dose and opioid receptor blockade, retention in treatment and illicit opioid drug use. Methods: Systematic review of the scientific literature through searches in the databases MEDLINE and PubMed. Results: The review of the opioid receptor blockade studies did not find evidence that a daily sublingual (SL) BUP tablet dose higher than 16 mg confers added blockade benefit, while doses under 8 mg are insufficient to produce opioid receptor blockade. The data are inconclusive regarding the relative effectiveness of an 8 mg SL BUP tablet dose versus a 16 mg SL BUP tablet dose in terms of opioid receptor blockade. The review did not establish any clear relationship between BUP dose and treatment retention or illicit opioid use. Conclusions: The BUP dose in treatment of OUD should be individualized based on a continuous clinical benefit-risk assessment. Further research is needed to better understand the relationship between dose and efficacy over time in patients with this complex disorder.

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 93%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Optimal dose of buprenorphine in opioid use disorder treatment: a review of pharmacodynamic and efficacy data

Hjelmström¹,

Nordbeck²,

Tiberg³

2020

Drug Development and Industrial Pharmacy

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“…Both regimens started with two consecutive monthly doses of 300 mg, followed by monthly maintenance doses of 100 mg (300/100 mg regimen) or 300 mg (300/300 mg regimen). At steady state, average plasma buprenorphine concentrations were 3.21 ng/mL and 6.54 ng/mL for the 300/100 mg and 300/300 mg regimens, respectively . As expected, BUP‐XR s.c. injection resulted in less fluctuation in plasma buprenorphine concentrations than after sublingual dosing, with lower peak concentrations (C max ) for similar level of exposure and a median time of maximum concentration (T max ) of ~ 24 hours .…”

Section: Summary Of Studies Included In Analysismentioning

confidence: 99%

Evaluation of the Effects of a Monthly Buprenorphine Depot Subcutaneous Injection on QT Interval During Treatment for Opioid Use Disorder

Schmith¹,

Curd²,

Lohmer³

et al. 2019

Clin Pharma and Therapeutics

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Extensive 12‐lead electrocardiogram monitoring and drug concentrations were obtained during development of BUP‐XR, a monthly subcutaneous injection for the treatment of opioid use disorder (OUD). Matched QT and plasma drug concentrations (11,925) from 1,114 subjects were pooled from 5 studies in OUD. A concentration‐QT model was developed, which accounted for confounding factors (e.g., comedications) affecting heart rate and heart rate‐corrected QT interval (QTc). Bias‐corrected nonparametric two‐sided 90% confidence intervals (CIs) were derived for the mean predicted effect of BUP‐XR on QTc (ΔQTc) at therapeutic and supratherapeutic doses. Changes in QTc were associated with age, central vs. noncentral reading, sex, methadone, and barbiturates. The upper 90% CI of ΔQTc was 0.29, 0.67, and 1.34 ms at the steady‐state peak concentration (Cmax) for 100, 300, and 2 × 300 mg doses, respectively. An effect of BUP‐XR on QT can be ruled out at therapeutic and supratherapeutic doses of BUP‐XR, after accounting for covariates that may influence heart rate and QT interval in OUD.

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Diagnosis and Treatment of Opioid Use Disorder in 2020

Wakeman

2020

JAMA

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In 2017, there were 47 506 opioid-related deaths in the United States. 1 Infectious complications from injecting opioids, such as hepatitis C, HIV, and endocarditis, result in additional morbidity and mortality. Understanding optimal approaches to screening for, diagnosing, and managing opioid use disorder (OUD), a chronic medical illness defined by an inability to control opioid use despite consequences, is necessary to address this condition. 2 ScreeningScreening instruments can help identify individuals at risk for or with OUD; however, no screening instruments exist specifically for OUD. Among screening instruments recommended by the National Institute on Drug Abuse (NIDA), 2 address opioid use among adults: the Tobacco, Alcohol, Prescription Medication, and Other Substance Use tool and the National Institute on Drug Abusemodified Alcohol, Smoking and Substance Involvement Screening Test. Use of these instruments in medical settings is limited by their length and complexity. An alternative approach is a single-item screening question, "How many times in the past year have you used an illegal drug or used a prescription medication for nonmedical reasons?" In primary care settings, a positive response to this question has a sensitivity of 85.1% and specificity of 88.6% for identifying drug use disorder. 3 This could be followed by asking the patient which drug(s) was used to identify whom to assess further for OUD.

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Efficacy and safety of a monthly buprenorphine depot injection for opioid use disorder: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Cited by 204 publications

References 24 publications

Optimal dose of buprenorphine in opioid use disorder treatment: a review of pharmacodynamic and efficacy data

Optimal dose of buprenorphine in opioid use disorder treatment: a review of pharmacodynamic and efficacy data

Evaluation of the Effects of a Monthly Buprenorphine Depot Subcutaneous Injection on QT Interval During Treatment for Opioid Use Disorder

Diagnosis and Treatment of Opioid Use Disorder in 2020

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