-
The Cochrane Database of Systematic... Feb 2017Managed withdrawal is a necessary step prior to drug-free treatment or as the endpoint of substitution treatment. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Managed withdrawal is a necessary step prior to drug-free treatment or as the endpoint of substitution treatment.
OBJECTIVES
To assess the effects of buprenorphine versus tapered doses of methadone, alpha-adrenergic agonists, symptomatic medications or placebo, or different buprenorphine regimens for managing opioid withdrawal, in terms of the intensity of the withdrawal syndrome experienced, duration and completion of treatment, and adverse effects.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 11, 2016), MEDLINE (1946 to December week 1, 2016), Embase (to 22 December 2016), PsycINFO (1806 to December week 3, 2016), and the Web of Science (to 22 December 2016) and handsearched the reference lists of articles.
SELECTION CRITERIA
Randomised controlled trials of interventions using buprenorphine to modify the signs and symptoms of withdrawal in participants who were primarily opioid dependent. Comparison interventions involved reducing doses of methadone, alpha-adrenergic agonists (clonidine or lofexidine), symptomatic medications or placebo, and different buprenorphine-based regimens.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane.
MAIN RESULTS
We included 27 studies involving 3048 participants. The main comparators were clonidine or lofexidine (14 studies). Six studies compared buprenorphine versus methadone, and seven compared different rates of buprenorphine dose reduction. We assessed 12 studies as being at high risk of bias in at least one of seven domains of methodological quality. Six of these studies compared buprenorphine with clonidine or lofexidine and two with methadone; the other four studies compared different rates of buprenorphine dose reduction.For the comparison of buprenorphine and methadone in tapered doses, meta-analysis was not possible for the outcomes of intensity of withdrawal or adverse effects. However, information reported by the individual studies was suggestive of buprenorphine and methadone having similar capacity to ameliorate opioid withdrawal, without clinically significant adverse effects. The meta-analyses that were possible support a conclusion of no difference between buprenorphine and methadone in terms of average treatment duration (mean difference (MD) 1.30 days, 95% confidence interval (CI) -8.11 to 10.72; N = 82; studies = 2; low quality) or treatment completion rates (risk ratio (RR) 1.04, 95% CI 0.91 to 1.20; N = 457; studies = 5; moderate quality).Relative to clonidine or lofexidine, buprenorphine was associated with a lower average withdrawal score (indicating less severe withdrawal) during the treatment episode, with an effect size that is considered to be small to moderate (standardised mean difference (SMD) -0.43, 95% CI -0.58 to -0.28; N = 902; studies = 7; moderate quality). Patients receiving buprenorphine stayed in treatment for longer, with an effect size that is considered to be large (SMD 0.92, 95% CI 0.57 to 1.27; N = 558; studies = 5; moderate quality) and were more likely to complete withdrawal treatment (RR 1.59, 95% CI 1.23 to 2.06; N = 1264; studies = 12; moderate quality). At the same time there was no significant difference in the incidence of adverse effects, but dropout due to adverse effects may be more likely with clonidine (RR 0.20, 95% CI 0.04 to 1.15; N = 134; studies = 3; low quality). The difference in treatment completion rates translates to a number needed to treat for an additional beneficial outcome of 4 (95% CI 3 to 6), indicating that for every four people treated with buprenorphine, we can expect that one additional person will complete treatment than with clonidine or lofexidine.For studies comparing different rates of reduction of the buprenorphine dose, meta-analysis was possible only for treatment completion, with separate analyses for inpatient and outpatient settings. The results were diverse, and we assessed the quality of evidence as being very low. It remains very uncertain what effect the rate of dose taper has on treatment outcome.
AUTHORS' CONCLUSIONS
Buprenorphine is more effective than clonidine or lofexidine for managing opioid withdrawal in terms of severity of withdrawal, duration of withdrawal treatment, and the likelihood of treatment completion.Buprenorphine and methadone appear to be equally effective, but data are limited. It remains possible that the pattern of withdrawal experienced may differ and that withdrawal symptoms may resolve more quickly with buprenorphine.It is not possible to draw any conclusions from the available evidence on the relative effectiveness of different rates of tapering the buprenorphine dose. The divergent findings of studies included in this review suggest that there may be multiple factors affecting the response to the rate of dose taper. One such factor could be whether or not the initial treatment plan includes a transition to subsequent relapse prevention treatment with naltrexone. Indeed, the use of buprenorphine to support transition to naltrexone treatment is an aspect worthy of further research.Most participants in the studies included in this review were male. None of the studies reported outcomes on the basis of sex, preventing any exploration of differences related to this variable. Consideration of sex as a factor influencing response to withdrawal treatment would be relevant research for selecting the most appropriate type of intervention for each individual.
Topics: Acute Disease; Buprenorphine; Clonidine; Female; Humans; Male; Methadone; Narcotic Antagonists; Opiate Substitution Treatment; Opioid-Related Disorders; Randomized Controlled Trials as Topic; Substance Withdrawal Syndrome
PubMed: 28220474
DOI: 10.1002/14651858.CD002025.pub5 -
JAMA Network Open May 2022Despite prevalent polysubstance use, treatment patterns and outcomes for individuals with opioid use disorder (OUD) and cooccurring substance use disorders (SUD) are... (Observational Study)
Observational Study
IMPORTANCE
Despite prevalent polysubstance use, treatment patterns and outcomes for individuals with opioid use disorder (OUD) and cooccurring substance use disorders (SUD) are understudied.
OBJECTIVE
To evaluate the distribution of buprenorphine and naltrexone initiation among individuals with OUD with vs without cooccurring SUD and to assess the comparative effectiveness associated with buprenorphine and naltrexone against drug-related poisonings.
DESIGN, SETTING, AND PARTICIPANTS
This observational comparative effectiveness study used insurance claims from 2011 to 2016 from the US IBM MarketScan databases to study initiation of medications for OUD (MOUD) among treatment-seeking individuals aged 12 to 64 years with a primary diagnosis of OUD. Cooccurring SUD was defined as SUD diagnosed concurrent with or in the 6 months prior to OUD treatment initiation. Treatment was codified as psychosocial treatment without MOUD or initiation or buprenorphine or naltrexone (including extended-release or oral). Methadone recipients were excluded from analysis. Data were analyzed from February 3, 2021, through February 26, 2022.
EXPOSURES
MOUD.
MAIN OUTCOMES AND MEASURES
Associations between cooccurring SUD diagnoses with treatment type were assessed with multivariable regression. The association of drug-related poisoning admissions with days covered with buprenorphine or naltrexone prescriptions vs days without prescriptions was assessed among MOUD initiators. Odds ratios from within-person fixed effects models were estimated as a function of MOUD and stratified by cooccurring SUDs.
RESULTS
Among 179 280 individuals with OUD (mean [SD] age, 33.2 [11.0] years; 90 196 [50.5%] men), 102 930 (57.4%) received psychosocial treatment without MOUD. Across 47 488 individuals with cooccurring SUDs, 33 449 (70.4%) did not receive MOUD, whereas across 131 792 individuals without cooccurring SUDs, 69 481 (52.7%) did not receive MOUD. Cooccurring SUD was associated with decreased odds of initiating buprenorphine (risk ratio [RR], 0.55 [95% CI, 0.54-0.56]) but increased odds of initiating naltrexone (extended release: RR, 1.12 [95% CI, 1.05-1.20]; oral: RR, 1.95 [95% CI, 1.86-2.03]). Among 12 485 individuals initiating MOUD who experienced at least 1 drug-related poisoning during insurance enrollment, buprenorphine treatment days were associated with decreased poisonings compared with days without MOUD for individuals with cooccurring SUD (odds ratio [OR], 0.56 [95% CI, 0.48-0.65]) and individuals without cooccurring SUD (OR, 0.57 [95% CI, 0.53-0.63]), with comparable associations observed for extended-release naltrexone. No protective association was observed for oral naltrexone.
CONCLUSIONS AND RELEVANCE
These findings suggest that individuals with OUD and polysubstance use were less likely to initiate buprenorphine and naltrexone than individuals without polysubstance use. Among individuals initiating MOUD, polysubstance use was associated with decreased buprenorphine and increased naltrexone initiation, despite buprenorphine's protective associations against drug-related poisoning.
Topics: Adult; Analgesics, Opioid; Buprenorphine; Female; Humans; Male; Naltrexone; Opiate Substitution Treatment; Opioid-Related Disorders
PubMed: 35536575
DOI: 10.1001/jamanetworkopen.2022.11363 -
Journal of Addiction MedicineAs overdose deaths from fentanyl continue to increase, optimizing use of medications for opioid use disorder has become increasingly important. Buprenorphine is a highly... (Review)
Review
OBJECTIVES
As overdose deaths from fentanyl continue to increase, optimizing use of medications for opioid use disorder has become increasingly important. Buprenorphine is a highly effective medication for reducing the risk of overdose death, but only if a patient remains in treatment. Shared decision making between prescribers and patients is important to establish a dose that meets each patient's treatment needs. However, patients frequently face a dose limit of 16 or 24 mg/d based on dosing guidelines on the Food and Drug Administration's package label.
METHODS
This review discusses patient-centered goals and clinical criteria for determining dose adequacy, reviews the history of buprenorphine dose regulation in the United States, examines pharmacological and clinical research results with buprenorphine doses up to 32 mg/d, and evaluates whether diversion concerns justify maintaining a low buprenorphine dose limit.
RESULTS
Pharmacological and clinical research results consistently demonstrate buprenorphine's dose-dependent benefits up to at least 32 mg/d, including reductions in withdrawal symptoms, craving, opioid reward, and illicit use while improving retention in care. Diverted buprenorphine is most often used to treat withdrawal symptoms and reduce illicit opioid use when legal access to it is limited.
CONCLUSIONS
In light of established research and profound harms from fentanyl, the Food and Drug Administration's current recommendations on target dose and dose limit are outdated and causing harm. An update to the buprenorphine package label with recommended dosing up to 32 mg/d and elimination of the 16 mg/d target dose would improve treatment effectiveness and save lives.
Topics: Humans; Buprenorphine; Analgesics, Opioid; Narcotic Antagonists; Opioid-Related Disorders; Fentanyl; Drug Overdose; Substance Withdrawal Syndrome
PubMed: 37788601
DOI: 10.1097/ADM.0000000000001189 -
Value in Health : the Journal of the... Feb 2021Buprenorphine is an essential medication for the treatment of opioid use disorder (OUD), but studies show it has been underused over the last 2 decades. We sought to...
OBJECTIVE
Buprenorphine is an essential medication for the treatment of opioid use disorder (OUD), but studies show it has been underused over the last 2 decades. We sought to evaluate utilization of and spending on buprenorphine formulations in Medicaid and to evaluate the impact of key market and regulatory factors affecting availability of different formulations and generic versions.
METHODS
We first identified all buprenorphine formulations approved by the Food and Drug Administration for OUD using Drugs@FDA. We then used National Drug Codes to identify each drug in the Medicaid State Drug Utilization Data and extracted annual utilization rates and spending between 2002 and 2018 by drug and according to whether a brand-name or generic version was dispensed. We compared these trends to market and regulatory factors that affected competition, which we identified through searching the Federal Register, Westlaw, PubMed, and Google News.
RESULTS
Brand-name buprenorphine-naloxone sublingual tablet and film formulations (Suboxone) were dispensed 2.7 times more (n = 634 213 140) and reimbursed 4.4 times more (n = $4 440 556 473) than all other formulations combined (n = 237 769 689; $1 018 988 133). We identified numerous market and regulatory factors that contributed to an estimated 9-year delay in generic versions of the tablet formulation and 6-year delay for generic versions of the film formulation.
CONCLUSIONS
Brand-name buprenorphine formulations have been widely used in Medicaid, leading to substantial costs, in part because generic versions were delayed by multiple years owing to market and regulatory factors. Timely availability of low-cost generics could have helped encourage OUD treatment with buprenorphine during the height of the opioid crisis.
Topics: Buprenorphine; Buprenorphine, Naloxone Drug Combination; Drug Utilization; Drugs, Generic; Economic Competition; Humans; Medicaid; Narcotic Antagonists; Opiate Substitution Treatment; Opioid-Related Disorders; Patents as Topic; United States
PubMed: 33518024
DOI: 10.1016/j.jval.2020.04.1840 -
Pain Management Jul 2020Buprenorphine is a Schedule III opioid with unique pharmacodynamic and pharmacokinetic properties that contribute to effective analgesia and fewer safety risks than... (Review)
Review
Buprenorphine is a Schedule III opioid with unique pharmacodynamic and pharmacokinetic properties that contribute to effective analgesia and fewer safety risks than other opioids. This review article focuses on the buccal film formulation, which is preferable to other buprenorphine formulations on the basis of bioavailability, safety and efficacy. The clinical studies reviewed here confirm that buprenorphine buccal film offers effective and continuous pain relief that is generally well tolerated, with no cases of respiratory depression reported in any of the studies. On the basis of these clinical data and individual patient risk/benefit assessments, clinicians should consider utilizing buprenorphine buccal film as a first-line opioid treatment for chronic pain over other buprenorphine formulations or other opioids.
Topics: Administration, Mucosal; Analgesics, Opioid; Buprenorphine; Cheek; Chronic Pain; Humans; Mouth Mucosa; Pain Management; Receptors, Opioid, mu
PubMed: 32394800
DOI: 10.2217/pmt-2020-0013 -
Journal of the American Board of Family... 2022The rate of overdose deaths has increased dramatically over the past 2 decades. Recently, efforts have been made to expand access to medications for opioid use disorder,...
The rate of overdose deaths has increased dramatically over the past 2 decades. Recently, efforts have been made to expand access to medications for opioid use disorder, such as buprenorphine, by removing X-waiver training requirements. However, relieving such barriers has also raised concern about increasing diversion rates for buprenorphine use, defined as the use of buprenorphine for some purpose or by someone other than it was originally intended. Historically, diversion has been addressed through the criminalization of buprenorphine possession without a prescription. We argue that while buprenorphine diversion is not to be condoned, the benefits of such actions greatly outweigh the harms. Thus, criminalization of diverted buprenorphine represents a dangerous and wasteful response that threatens the progress made through expanded access to this lifesaving medication.
Topics: Buprenorphine; Drug Overdose; Humans; Instinct; Opioid-Related Disorders
PubMed: 35379727
DOI: 10.3122/jabfm.2022.02.210308 -
The International Journal on Drug Policy Jul 2022Structural vulnerabilities for people who use drugs (PWUD) were exacerbated by the COVID-19 pandemic. In this context, federal lawmakers in the United States (U.S.)...
BACKGROUND
Structural vulnerabilities for people who use drugs (PWUD) were exacerbated by the COVID-19 pandemic. In this context, federal lawmakers in the United States (U.S.) invoked an exemption to the 2008 Ryan Haight Act requiring in-person evaluation to prescribe buprenorphine for treatment of opioid use disorder (OUD), which allowed for the initiation and maintenance of buprenorphine via telehealth. Despite the potential for telehealth to address some of the geographic disparities in OUD treatment access, recent research has suggested that significant barriers to buprenorphine also exist at the pharmacy level. The purpose of this study was to qualitatively assess how efforts to increase access to buprenorphine via telehealth are implemented by prescribers and pharmacists and experienced by patients.
METHODS
Participant observation and semi-structured interviews focused on telehealth for OUD treatment and buprenorphine prescribing and dispensing were conducted with patients (n = 19), prescribers and clinic staff (n = 24), and pharmacists (n = 10) in Pennsylvania and California between May 2020 - May 2021.
FINDINGS
While participants stated that telehealth for OUD treatment was a welcome option, pharmacy-level barriers to buprenorphine persisted. Geographical distance from patient to provider or pharmacist continued to serve as "red flags" for pharmacists, leading to pharmacy-level "red tape:" gatekeeping measures including geographic restrictions, telephone prescription "confirmations," prescription cancellations and refusals. Patients' unmet expectations of buprenorphine access in some cases led to unanticipated risks including a return to injection drug use.
CONCLUSION
Challenges to increasing buprenorphine access persist in the U.S. even in settings where telehealth is implemented, and telehealth may inadvertently produce new barriers for some patients. Despite national support for policies aimed at increasing access to treatment for substance use disorders rather than punishment, policy shifts from punishment to treatment have not permeated evenly across all geographic areas and populations. Perceived threats of Drug Enforcement Administration (DEA) enforcement, and self-defensive institutional practices in pharmacies, reinforce ideologies of drug law enforcement, leading to poor patient outcomes including lack of buprenorphine access.
Topics: Humans; Buprenorphine; COVID-19 Drug Treatment; Opiate Substitution Treatment; Opioid-Related Disorders; Pandemics; Pharmacies; Pharmacy; Telemedicine; United States
PubMed: 35561484
DOI: 10.1016/j.drugpo.2022.103703 -
American Journal of Veterinary Research Mar 2017OBJECTIVE To determine pharmacokinetics and pharmacodynamics of buprenorphine after IV and SC administration and of sustained-release (SR) buprenorphine after SC...
OBJECTIVE To determine pharmacokinetics and pharmacodynamics of buprenorphine after IV and SC administration and of sustained-release (SR) buprenorphine after SC administration to adult alpacas. ANIMALS 6 alpacas. PROCEDURES Buprenorphine (0.02 mg/kg, IV and SC) and SR buprenorphine (0.12 mg/kg, SC) were administered to each alpaca, with a 14-day washout period between administrations. Twenty-one venous blood samples were collected over 96 hours and used to determine plasma concentrations of buprenorphine. Pharmacokinetic parameters were calculated by use of noncompartmental analysis. Pharmacodynamic parameters were assessed via sedation, heart and respiratory rates, and thermal and mechanical antinociception indices. RESULTS Mean ± SD maximum concentration after IV and SC administration of buprenorphine were 11.60 ± 4.50 ng/mL and 1.95 ± 0.80 ng/mL, respectively. Mean clearance was 3.00 ± 0.33 L/h/kg, and steady-state volume of distribution after IV administration was 3.8 ± l.0 L/kg. Terminal elimination half-life was 1.0 ± 0.2 hours and 2.7 ± 2.8 hours after IV and SC administration, respectively. Mean residence time was 1.3 ± 0.3 hours and 3.6 ± 3.7 hours after IV and SC administration, respectively. Bioavailability was 64 ± 28%. Plasma concentrations after SC administration of SR buprenorphine were below the LLOQ in samples from 4 alpacas. There were no significant changes in pharmacodynamic parameters after buprenorphine administration. Alpacas exhibited mild behavioral changes after all treatments. CONCLUSIONS AND CLINICAL RELEVANCE Buprenorphine administration to healthy alpacas resulted in moderate bioavailability, rapid clearance, and a short half-life. Plasma concentrations were detectable in only 2 alpacas after SC administration of SR buprenorphine.
Topics: Animals; Buprenorphine; Camelids, New World; Delayed-Action Preparations; Female; Half-Life; Heart Rate; Male; Respiratory Rate
PubMed: 28240955
DOI: 10.2460/ajvr.78.3.321 -
Drug and Alcohol Dependence Nov 2017Maternal buprenorphine maintenance predisposes the infant to exhibit neonatal abstinence syndrome (NAS), but there is insufficient published information regarding the...
BACKGROUND AND OBJECTIVES
Maternal buprenorphine maintenance predisposes the infant to exhibit neonatal abstinence syndrome (NAS), but there is insufficient published information regarding the nature of NAS and factors that contribute to its severity in buprenorphine-exposed infants.
METHODS
The present study evaluated forty-one infants of buprenorphine-maintained women in comprehensive substance use disorder treatment who participated in an open-label study examining the effects of maternal buprenorphine maintenance on infant outcomes. Modifiers of the infant outcomes, including maternal treatment and substance use disorder parameters, were also evaluated.
RESULTS
Fifty-nine percent of offspring exhibited NAS that required pharmacologic management. Both maternal buprenorphine dose as well as prenatal polysubstance exposure to illicit substance use/licit substance misuse were independently associated with NAS expression. Polysubstance exposure was associated with more severe NAS expression after controlling for the effects of buprenorphine dose. Other exposures, including cigarette smoking and SRI use, were not related to outcomes. Maternal buprenorphine dose was positively associated with lower birth weight and length.
CONCLUSIONS
Polysubstance exposure was the most potent predictor of NAS severity in this sample of buprenorphine-exposed neonates. This finding suggests the need for interventions that reduce maternal polysubstance use during medication assisted treatment for opioid use disorder, and highlights the necessity of a comprehensive approach, beyond buprenorphine treatment alone, for the optimal care for pregnant women with opioid use disorders.
Topics: Buprenorphine; Female; Humans; Infant, Newborn; Methadone; Neonatal Abstinence Syndrome; Opiate Substitution Treatment; Opioid-Related Disorders; Pregnancy; Pregnancy Complications
PubMed: 28869859
DOI: 10.1016/j.drugalcdep.2017.08.001 -
Journal of the American Association For... Mar 2022Sustained-release formulations of controlled substances are commonly used to provide analgesia in research animals. These formulations represent refinements that offer...
Sustained-release formulations of controlled substances are commonly used to provide analgesia in research animals. These formulations represent refinements that offer the advantage of prolonged, multiday pain relief with a single injection, thereby decreasing handling stress in animals and saving time for scientists. Compounding pharmacies produce sustainedrelease buprenorphine for veterinary use (i. e., buprenorphine SR-LAB); one of these pharmacies has shortened the original 6-mo shelf-life to 28 d to comply with United States Pharmacopeia standards for ensuring sterility. This limitation risks increasing the waste of controlled substances, which require an expensive destruction process that is legally enforced in our state. To assess whether the sterility of buprenorphine SR-LAB is preserved for at least 6 mo in a general laboratory setting, we tested 5 bottles for the presence of endotoxin and bacterial and fungal contamination monthly for 6 mo. Overall, results of the study showed that the bottles remained sterile over the 6-mo duration as no endotoxin was detected and the bottles did not become contaminated with bacteria or fungi. In conclusion, when stored securely and used with aseptic handling techniques, buprenorphine SR-LAB can be maintained in a sterile state for 6 mo in a general laboratory setting.
Topics: Analgesics, Opioid; Animals; Buprenorphine; Delayed-Action Preparations; Infertility; Pain
PubMed: 35082006
DOI: 10.30802/AALAS-JAALAS-21-000105