Buprenorphine–naloxone buccal soluble film for the treatment of opioid dependence: current update

Introduction: Opioid dependence is a severe medical disorder with a high psychiatric and somatic comorbidity and mortality rate. The opioid agonist methadone, mixed agonist-antagonist buprenorphine and the combination of buprenorphine with the opioid antagonist naloxone are the first-line maintenance treatments for opioid dependence. Risk of diversion and accidental intoxications, especially in children, are of great concern. To lower these risks, a novel buprenorphine–naloxone film has been developed and introduced in the USA and Australia.

Areas covered: This review evaluates the available preclinical and clinical data on the novel buprenorphine–naloxone film for treatment of opioid dependence. Literature was identified through a comprehensive PubMed search. Data sources also included official FDA information and material made public by the manufacturer.

Expert opinion: Few preclinical and clinical data on safety and efficacy have been published. The pharmacological differences between the novel film and the conventional buprenorphine/naloxone are small. In an experimental study, the new formulation suppressed symptoms of opioid withdrawal. The spectrum of adverse events seems to be similar to that of the conventional sublingual tablet. Recent data show that patients prefer the novel film over the conventional sublingual tablet. Emerging surveillance data indicate a lower risk of accidental poisoning in children compared with the conventional formulation. Further clinical and preclinical data are needed to explore additional possible advantages of the new formulation.     

Book review of the psychodynamics of addiction by Martin Weegmann & Robert Cohen London: whurr publishers 2002, 180 pp. £19.50, ISBN 1 86156 335 3

Aims: To ascertain the level of knowledge about some of the effects of methadone and buprenorphine among 956 clients receiving treatment for opioid dependence at 9 public clinics and 50 community pharmacies in New South Wales, Australia.

Methods: A cross-sectional survey using both research-administered and self-complete questionnaires assessed medication-specific knowledge (derived from a literature review and information contained within client treatment information booklets), answered only by those receiving that treatment type. Assessment of knowledge was performed by asking participants to agree or disagree with four statements about their medication.

Findings: The majority of methadone clients were aware of the risks of overdose when methadone is taken by non-tolerant people and when methadone is mixed with other CNS depressants. Methadone clients were less aware of the protective effects of methadone in overdose and most believed that it rotted their teeth. Almost 50% of those on buprenorphine were not aware of the effects of dose increase on duration of action nor its relatively good safety profile compared to methadone. Buprenorphine clients were well informed about the importance of sublingual absorption and the risks of precipitated withdrawal.

Conclusions: This study identifies significant gaps in the knowledge that opioid-dependent clients have about methadone and buprenorphine that may lead to suboptimal use of medications and ambivalence over treatment. In addition to the provision of written material service providers need to consider systems to ensure that clinical information concerning treatment is received and understood by clients.     

Buprenorphine and buprenorphine/naloxone soluble-film for treatment of opioid dependence

Introduction: Opioid dependence is a chronic relapsing disorder that shows excess mortality and comorbidity with somatic and psychiatric disorders. Methadone and buprenorphine/naloxone are widely accepted and are used as first-line maintenance treatments for opioid dependence. Fatal intoxications with these agents, risk of diversion, and accidental intoxications, especially in children, are apparent risks and are of increasing public concern. Buprenorphine/naloxone sublingual tablet is an established treatment for opioid dependence. A novel buprenorphine/naloxone film has been developed with improved pharmacokinetics and a hopefully lower risk of diversion and accidental intoxications.

Areas covered: This review evaluates the available preclinical and clinical data on the novel buprenorphine/naloxone film for the treatment of opioid dependence. Literature was identified though a comprehensive PubMed search and data sources included official FDA information.

Expert opinion: This is an interesting new formulation of a well-established medication in opioid dependence. However, few data have been published on its safety and efficacy. In an experimental study, the new formulation suppressed symptoms of opioid withdrawal as expected. Results of an unpublished study made public by the FDA suggest a spectrum of adverse events similar to that of the conventional sublingual tablet. Some data show patients may prefer the novel film over the sublingual tablet. The estimated lower risk for diversion and especially for accidental poisoning in children cannot be assessed in clinical studies but requires data from emergency room visits.     

Drug interactions between buprenorphine,methadone and hepatitis C therapeutics

Introduction: People who inject drugs (PWID) and other individuals with opioid use disorders have a dramatically higher prevalence of hepatitis C virus (HCV) infection than the general population. The availability of novel direct acting antivirals (DAAs) for the treatment of HCV infection with very high efficacy, improved tolerability and shortened treatment durations have led to global efforts to ramp up treatment for all HCV-infected individuals to prevent or delay complications of the disease. Individuals with opioid use disorders, including those on medication-assisted therapy such as methadone or buprenorphine, are a key demographic group that can benefit from HCV treatment given their high HCV prevalence; however, pharmacokinetic and pharmacodynamic drug interactions could blunt their utility.

Areas covered: We performed a comprehensive literature review of published and unpublished data from PubMed database, relevant conference abstracts/proceedings and FDA approved drug package inserts, to review the pharmacokinetic (PK) profile and drug interactions between currently approved HCV DAAs and methadone and buprenorphine.

Expert opinion: The paper highlights specific drug combinations which result in altered opioid drug levels including telaprevir/methadone, daclatasvir/buprenorphine, and Abbvie 3D combination regimen (paritaprevir, ritonavir, ombitasvir and dasabuvir)/buprenorphine. However, concurrent pharmacodynamics assessments did not reveal significant signs and symptoms of opioid withdrawal or toxicity that would preclude concurrent administration.     

Consideration of opioid agonist treatment in a pregnant adolescent: A case report and literature review

Abstract

Background: Opioid use greatly increases the risk of overdose death, as well as contracting human immunodeficiency virus (HIV) and hepatitis. Opioid agonist treatment is recommended for pregnant women who are dependent on opioids. However, there is a dearth of studies on the use of opioid agonist treatment in pregnant teenagers. Case: Ms. A, a 15?year-old G1PO in foster care, presented to our tertiary women’s hospital requesting opioid agonist treatment for use of pill opioids. She reported nasal inhalation of 5–6 opioid tablets daily, with recent attempts to self-taper using nonprescribed buprenorphine since learning of her pregnancy. Last reported opioid use was >24?hours prior to admission. Urine drug testing was positive only for opioids (negative for buprenorphine and methadone). She did not exhibit significant withdrawal symptoms while hospitalized. The psychiatric treatment team recommended deferring opioid agonist treatment and pursuing outpatient substance use treatment. Unfortunately, Ms. A did not attend outpatient treatment and was lost to follow up. Discussion: Based upon our experience and review of the studies regarding opioid use disorder (OUD) and perinatal and adolescent opioid use, we recommend that pregnant adolescents with OUD be referred to opioid agonist treatment with buprenorphine or methadone. Studies specifically addressing opioid agonist treatment in pregnant teenagers are needed.     

Addiction Diagnostic Update: DSM-III-R Psychoactive Substance Use Disorders

Abstract

This article reviews the Community Reinforcement Approach (CRA) in the treatment of opioid dependence. It covers the use of CRA with both methadone maintenance patients and patients withdrawing from opioids. The data reviewed in the use of CRA in combination with methadone maintenance shows improvement in a number of areas. These include the reduction of opioid use, as well as other drugs of abuse, improved legal status, less psychiatric symptoms, and improved vocational and social functioning. CRA coupled with vouchers can assist in retaining patients in treatment long enough to improve opioid detoxification rates from buprenorphine and coupled with naltrexone may sustain abstinence. Further, the use of a standardized computerized format may extend the utility of CRA.     

Effects of buprenorphine and methadone in methadone-maintained subjects

Buprenorphine, a partial mu opioid agonist, is an experimental medication under development for the treatment of opioid dependence as an alternative to methadone maintenance. The present study examined the relationship between level of opioid physical dependence and response to buprenorphine administration as part of a program to develop procedures for transferring patients from methadone to buprenorphine treatment. This laboratory study characterized the agonist and antagonist effects of acute doses of buprenorphine and methadone in subjects maintained on either 30 (n=7) or 60 (n=6) mg/day oral methadone. Test doses of placebo [sl. and PO), methadone (15, 30, and 60 mg PO) and buprenorphine (2, 4, and 8 mg sl.) were administered to volunteers residing on a closed residential unit. Subjective, physiological, observer-rated, and cognitive/psychomotor measures were collected for 6.5 h after test doses. Test doses of methadone, but not buprenorphine, constricted pupils and produced dose-related increases on subjective report measures reflecting opioid agonist drug effects. Agonist effects of methadone were more prominent in the 30 mg than in the 60 mg methadone maintenance condition. Buprenorphine, but not methadone, precipitated opioid withdrawal signs and symptoms that were more prominent in the 60 mg than in the 30 mg methadone maintenance condition. These findings suggest that abrupt transition from methadone to buprenorphine may produce patient discomfort that is positively related to both methadone maintenance dose and buprenorphine transition dose.     

Buprenorphine: a controlled clinical trial in the treatment of opioid dependence

Clinical trials carried out to compare methadone and buprenorphine in the treatment of opioid dependence have generally employed an alcoholic solution of buprenorphine, which has a bioavailability superior to that of the tablets. Since the product available for large scale use is in tablet form, one intended to verify the efficacy of this formulation. In a multicentre randomised controlled double blind study, 72 opioid dependent patients were assigned to treatment with buprenorphine (8 mg/day) or methadone (60 mg/day) for a period of 6 months. The two compounds did not show any significant difference with regard to urinalyses: the average percentage of analyses proving negative was 60.4% for patients assigned to buprenorphine, and 65.5% for those assigned to methadone. With regard to retention, a non-significant trend in favour of methadone was observed. Patients completing the trial improved significantly in terms of psychosocial adjustment and global functioning, as ascertained by the DSM-IV-GAF and symptom checklist-90 (SCL-90) scales, and this was independent of the treatment group. Finally, in the case of buprenorphine, patients who dropped out differed significantly from those who stayed, in terms of a higher level of psychopathological symptoms, and a lower level of psychosocial functioning. The results of the study further support the utility of buprenorphine for the treatment of opioid dependence.     

Update on pharmacotherapy for treatment of opioid use disorder

Introduction: Opioid Use Disorder (OUD) is a significant public health concern, negatively impacting the medical, psychological, and social domains of an individual’s life as well as creating substantial burdens for society. Effective treatment interventions are necessary for reduction of OUD and its consequences. Pharmacotherapy represents a central component of management.

Areas covered: This review focuses on pharmacologic strategies for OUD treatment, discussing both primary as well as adjunctive therapy modalities. We will discuss both medications used during detoxification to treat withdrawal, as well as those used as maintenance therapy. Detox medications include alpha-2 adrenergic agonists, such as clonidine, as well as the μ-opioid agonist, methadone, and the μ-opioid partial agonist, buprenorphine. Opioid maintenance treatment (OMT) is also discussed, focusing on those medications meant to substitute abused opioids and includes the agonists, methadone and buprenorphine, as well as supervised intravenous heroin, and opioid antagonist, naltrexone.

Expert opinion: Medication therapy for treatment of OUD has demonstrated efficacy and is of great clinical benefit. While agonist treatment with methadone or buprenorphine remains the gold standard, there is an important place for use of long-acting antagonist therapy with naltrexone. Continued investigation into treatment paradigms and behavioral platforms which optimize medication therapy is most needed.     

Book Review of Alcohol,Drugs and Health Promotion in Modern Ireland Shane Butler. By Dublin: Institute of Public Administration, 260 pp., €30 (pbk), ISBN 1 902448 77 4

Aims: There are currently 39,000 people on methadone or buprenorphine treatment in Australia, representing approximately one third of the opioid-dependent population. An educational DVD, entitled Access All Areas, was developed to inform, attract and engage opioid-dependent drug users into treatment, with a view to increasing users’ understanding of the benefits and risks of treatment and factors impacting the way treatment is delivered.

Methods: A pilot evaluation of the draft DVD was conducted with 99 opioid users recruited from two public opioid treatment clinics and four Needle Syringe Programs (NSP). Participants viewed a 1-hour segment of the DVD and completed a pre- and post-test knowledge questionnaire, and an evaluation questionnaire.

Findings: After viewing the DVD, the majority of participants had a ‘better understanding of the benefits of treatment’ (95%), and were ‘more likely to ask about hepatitis C treatment’ (69%). Among participants not on opioid treatment, 37% were ‘more interested in the idea of treatment’ after viewing the DVD. The mean number of correct responses to knowledge questions increased marginally after viewing the DVD (14/28 vs. 15/28; p <.05). However, there were considerable increases in the proportion of participants who responded correctly to questions regarding pregnancy and opioids, the dental effects of methadone, and hepatitis.

Conclusions: This study provides preliminary evidence of the benefits of this educational resource to people with opioid dependence. Future research is planned evaluating the DVD in a controlled trial exploring treatment engagement, retention, and other outcomes.     

Fatal and non-fatal opioid overdose in opioid dependent patients treated with methadone,buprenorphine or implant naltrexone

BackgroundIllicit opioid use is associated with high rates of fatal and non-fatal opioid overdose. This study aims to compare rates of fatal and serious but non-fatal opioid overdose in opioid dependent patients treated with methadone, buprenorphine or implant naltrexone, and to identify risk factors for fatal opioid overdose.MethodsOpioid dependent patients treated with methadone (n = 3515), buprenorphine (n = 3250) or implant naltrexone (n = 1461) in Western Australia for the first time between 2001 and 2010, were matched against state mortality and hospital data. Rates of fatal and non-fatal serious opioid overdoses were calculated and compared for the three treatments. Risk factors associated with fatal opioid overdose were examined using multivariate cox proportional hazard models.ResultsNo significant difference was observed between the three groups in terms of crude rates of fatal or non-fatal opioid overdoses. During the first 28 days of treatment, rates of non-fatal opioid overdose were high in all three groups, as were fatal opioid overdoses in patients treated with methadone. However, no fatal opioid overdoses were observed in buprenorphine or naltrexone patients during this period. Following the first 28 days, buprenorphine was shown to be protective, particularly in terms of non-fatal opioid overdoses. After the cessation of treatment, rates of fatal and non-fatal opioid overdoses were similar between the groups, with the exception of lower rates of non-fatal opioid overdose in the naltrexone treated patients compared with the methadone treated patients. After the commencement of treatment, gender, and hospitalisations with a diagnosis of opioid poisoning, cardiovascular or mental health problems were significant predictors of subsequent fatal opioid overdose.ConclusionsRates of fatal and non-fatal opioid overdose were not significantly different in patients treated with methadone, buprenorphine or implant naltrexone. Gender and prior cause-specific hospitalisations can be used to identify patients at a high risk of fatal opioid overdose.     

Buprenorphine versus methadone in the treatment of opioid-dependent cocaine users

This study compared the efficacy of buprenorphine to methadone for decreasing cocaine use in patients with combined opioid and cocaine use. Participants (n=51) were enrolled in a 26-week treatment program and randomly assigned to either buprenorphine or methadone. Dosing was double-blind and double-dummy. Patients were stabilized on either 8 mg sublingual buprenorphine or 50 mg oral methadone, with dose increases given in response to continued illicit cocaine use or opioid use through week 16 of treatment. Maximum doses possible were 16 mg buprenorphine and 90 mg methadone. Average doses achieved were 11.2 mg buprenorphine and 66.6 mg methadone; 49% of the patients received the maximum doses possible. Urine samples were collected three times per week, and there was no significant difference in the rate of cocaine positive urines for the intent-to-treat sample (69% for buprenorphine versus 63% for methadone). For patients who remained in treatment through the flexible dosing period (n=28), there were significant decreases in cocaine positive urines over time (P<0.01), but no significant differences between groups or group × time effects. Buprenorphine and methadone were equally effective on measures of treatment retention, urine results for opioids, and compliance with attendance and counseling. These results demonstrate no selective efficacy of either buprenorphine or methadone in attenuating cocaine use in this population, but do provide further support for the equivalent efficacy of buprenorphine and methadone in the treatment of opioid dependence.Presented at the 55th Annual Scientific Meeting, The College on Problems of Drug Dependence, Toronto, Canada (Mune 17, 1993)     

Buprenorphine versus methadone maintenance: a cost-effectiveness analysis

This article presents the cost-effectiveness results of a randomised controlled trial conducted in two Australian cities. The trial was designed to assess the safety, efficacy and cost-effectiveness of buprenorphine versus methadone in the management of opioid dependence. The trial utilised a flexible dosing regime that was tailored to the clinical need of the patients, with high maximum doses, using the marketed formulation, under double-blind conditions. A total of 405 subjects were randomised to a treatment at one of three specialist outpatient drug treatment centres in Adelaide and Sydney, Australia. The perspective of the cost-effectiveness analysis was that of the service provider and included costs relevant to the provision of treatment. The primary outcome measure used in the economic analysis was change in heroin-free days from baseline to the sixth month of treatment. Treatment with methadone was found to be both less expensive and more effective than treatment with buprenorphine, which suggests methadone dominates buprenorphine. However, statistical testing found that the observed difference between the cost-effectiveness of methadone and buprenorphine treatments was not statistically significant. The results of this study provide useful policy information on the costs and outcomes associated with the use of methadone and buprenorphine and indicate that buprenorphine provides a viable alternative to methadone in the treatment of opioid dependence.     

Pain Is Not Associated with Worse Office-Based Buprenorphine Treatment Outcomes

ABSTRACT

Physical pain is common among individuals seeking treatment for opioid dependence. Pain may negatively impact addiction treatment. The authors prospectively studied opioid-dependent individuals initiating office-based buprenorphine treatment, comparing buprenorphine treatment outcomes (treatment retention and opioid use) among participants with and without pain (baseline pain or persistent pain). Among 82 participants, 60% reported baseline pain and 38% reported persistent pain. Overall, treatment retention was 56% and opioid use decreased from 89% to 26% over 6 months. In multivariable analyses, the authors found no association between pain and buprenorphine treatment outcomes. Opioid-dependent individuals with and without pain can achieve similar success with buprenorphine treatment.     

Buprenorphine dosing choices in specific populations: review of expert opinion

Introduction: Treatment of opioid dependence with buprenorphine improves outcomes. Typical dosing ranges for all patients from clinical evidence and as defined in the product information are wide. For specific groups with complex clinical scenarios, there is no clear consensus on dosing choices to achieve best possible outcomes.

Areas covered: The doses of buprenorphine used in 6 European countries was reviewed. A review of published evidence supported rapid induction with buprenorphine and the benefits of higher doses but did not identify clearly useful guidance on dosing choices for groups with complex clinical scenarios. An expert group of physicians with experience in addiction care participated in a discussion meeting to share clinical practice experience and develop a consensus on dosing choices.

Expert opinion: There was general agreement that treatment outcomes can be improved by optimising buprenorphine doses in specific subgroups. Specific groups in whom buprenorphine doses may be too low and who could have better outcomes with optimised dosing were identified on the basis of clinical practice experience. These groups include people with severe addiction, high tolerance to opioids, and psychiatric comorbidities. In these groups it is recommended to review dosing choices to ensure buprenorphine dosing is sufficient.     

A Buprenorphine Education and Training Program for Primary Care Residents: Implementation and Evaluation

ABSTRACT. Background: Although substance use disorders are highly prevalent, resident preparation to care for patients with these disorders is frequently insufficient. With increasing rates of opioid abuse and dependence, and the availability of medication-assisted treatment, one strategy to improve resident skills is to incorporate buprenorphine treatment into training settings. Methods: In this study, esidency faculty delivered the BupEd education and training program to 71 primary care residents. BupEd included (1) a didactic session on buprenorphine, (2) an interactive motivational interviewing session, (3) monthly case conferences, and (4) supervised clinical experience providing buprenorphine treatment. To evaluate BupEd, the authors assessed (1) residents’ provision of buprenorphine treatment during residency, (2) residents’ provision of buprenorphine treatment after residency, and (3) treatment retention among patients treated by resident versus attending physicians. Results: Of 71 residents, most served as a covering or primary provider to at least 1 buprenorphine-treated patient (84.5 and 66.2%, respectively). Of 40 graduates, 27.5% obtained a buprenorphine waiver and 17.5% prescribed buprenorphine. Treatment retention was similar between patients cared for by resident PCPs versus attending PCPs (90-day retention: 63.6% [n = 35] vs. 67.9% [n = 152]; P = .55). Conclusion: These results show that BupEd is feasible, provides residents with supervised clinical experience in treating opioid-dependent patients, and can serve as a model to prepare primary care physicians to care for patients with opioid dependence.