Urine naloxone concentration at different phases of buprenorphine maintenance treatment

In spite of the benefits of buprenorphine‐naloxone co‐formulation (BNX) in opioid maintenance treatment, the naloxone component has not prevented parenteral use of BNX. Current laboratory methods are not sufficient to differentiate between therapeutic and illicit use of buprenorphine, and little is known about urine naloxone concentrations. Measurement of urine naloxone, together with buprenorphine and norbuprenorphine, might help to determine the naloxone source and administration route. A liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) method was developed and validated for this purpose. Naloxone, buprenorphine, and norbuprenorphine total concentrations were measured in urine samples from opioid‐dependent patients before and during stable and unstable phases of maintenance treatment with BNX. The limit of quantification in urine was 1.0 µg/L for naloxone, buprenorphine and norbuprenorphine. Before treatment, all samples contained buprenorphine but the median naloxone concentration was 0 µg/L. During the maintenance treatment with BNX all urine samples were positive for naloxone, buprenorphine and norbuprenorphine. The naloxone concentration at a stable phase of treatment (median 60 µg/L, range 5–200 µg/L) was not different from the naloxone concentration at an unstable phase (70 µg/L, 10–1700 µg/L). Applying an upper limit of 200 µg/L to the sample, the median naloxone/buprenorphine ratio was higher in the high than in the low naloxone concentration group (0.9 vs 0.3, respectively). This study suggests that naloxone in urine can act as an indicator of compliance with BNX. Parenteral use of BNX was associated with a high naloxone/buprenorphine ratio. Negative naloxone with positive buprenorphine suggests the use/abuse of buprenorphine alone. Copyright © 2013 John Wiley & Sons, Ltd.     

Pain management in opioid maintenance treatment

ABSTRACT

Introduction: Opioid addiction is a worldwide disease with a significant impact. A multitude of physical and mental comorbidities are associated with opioid addiction, pain being one of the most relevant. Insufficient pain management may lead to a disruption in medical treatment, self-medication, and subsequent harm to patients.

Areas covered: In this review, the authors provide a general overview of opioid addiction. A literature search for pain management and opioid maintenance treatment was conducted. Different settings of acute or chronic pain and situations specific to patients addicted to opioids are described. Pain management therapy in addiction is also addressed with an emphasis on treatment strategies such as the optimization of methadone and buprenorphine medication, additional opioid analgesia, and multimodal pain management.

Expert opinion: Opioid addiction is a growing global health concern, and maintenance therapy remains an effective and lifesaving treatment option. However, there remains uncertainty on the appropriate pain management for this patient group. The backbone of pain management in opiate-addicted patients remains maintenance therapy while adjunctive treatment such as regional analgesia, non-opioid analgesia, antidepressants, steps to improve sleep, acceptance and commitment therapy, biofeedback, and hypnosis should be considered. Additional opioid medication is possible as well.     

Managing opioid withdrawal precipitated by buprenorphine with buprenorphine

Buprenorphine is a partial opioid agonist commonly used to treat opioid dependence. The pharmacology of buprenorphine increases the risk of a precipitated opioid withdrawal when commencing patients on buprenorphine treatment, particularly when transferring from long acting opioids (e.g. methadone). There is little documented experience regarding the management of precipitated withdrawal. In our case, a patient developed a significant precipitated opioid withdrawal following buprenorphine administration, and was able to be successfully treated in hospital with further buprenorphine. This demonstrates that rapid increases in buprenorphine dose can be used as an effective treatment for buprenorphine-induced precipitated opioid withdrawal. The use of buprenorphine to manage withdrawal then allows the individual to continue on this highly effective treatment.     

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.     

High‐dose buprenorphine for treatment of high potency opioid use disorder

A 29‐year‐old woman presented to detox for treatment of an opioid use disorder with illicit fentanyl. While in detox, she was started on opioid agonist treatment with buprenorphine/naloxone. Unfortunately, she continued to have withdrawal symptoms despite being optimised to a dose of 32 mg. She was given additional PRNs of buprenorphine/naloxone to a total daily dose of 40 mg, which helped to alleviate her symptoms of withdrawal and cravings. She was stabilised on buprenorphine/naloxone 40 mg daily without any side effects and was discharged to a rehabilitation centre.     

Efficacy and safety of a sublingual buprenorphine/naloxone rapidly dissolving tablet for the treatment of adults with opioid dependence: A randomized trial

This prospective, randomized, active-controlled, non-inferiority study evaluated the efficacy and safety of a sublingual buprenorphine/naloxone rapidly dissolving tablet (Zubsolv^®; buprenorphine/naloxone rapidly dissolving tablet) versus generic buprenorphine for induction of opioid maintenance among dependent adults. The study, conducted at 13 sites from June 2013 to January 2014, included a 2-day blinded induction phase and a 27-day open-label stabilization/maintenance phase. During the blinded induction, patients received fixed doses of buprenorphine/naloxone rapidly dissolving tablets or generic buprenorphine. During open-label stabilization/early maintenance, all patients received buprenorphine/naloxone rapidly dissolving tablets. The primary efficacy assessment was treatment retention at day 3; buprenorphine/naloxone rapidly dissolving tablets were considered non-inferior to generic buprenorphine if the lower limit of the 95% confidence interval for the difference between the treatments was ≥–10% in patients retained on day 3. Secondary assessments included opioid withdrawal symptoms and cravings as measured using the Clinical Opiate Withdrawal Scale, the Subjective Opiate Withdrawal Scale, and the opioid cravings visual analogue scale. Safety was also assessed. A total of 313 patients were randomly assigned to induction with generic buprenorphine or buprenorphine/naloxone rapidly dissolving tablets. The mean age was 38.4 years, and the mean duration of opioid dependence was 12.4 years. For the primary efficacy assessment, 235 of 256 patients (91.8%) were retained at day 3 and continued to the maintenance phase. The lower limit of the 95% confidence interval was ?13.7; thus, buprenorphine/naloxone rapidly dissolving tablets did not demonstrate non-inferiority to generic buprenorphine, and significantly more patients who received induction with generic buprenorphine (122/128 [95.3%]) were retained at day 3 compared with those who received induction with buprenorphine/naloxone rapidly dissolving tablets (113/128 [88.3%]; 95% confidence interval: ?13.7, ?0.4; p = 0.040). The rates of clinical response, as measured by the Clinical Opiate Withdrawal Scale, the Subjective Opiate Withdrawal Scale, and the visual analogue scale, were comparable among patients regardless of the induction medication. Treatment with buprenorphine/naloxone rapidly dissolving tablets was generally safe and reduced the severity of withdrawal symptoms and cravings.     

Buprenorphine alone and in combination with naloxone in non-dependent humans

This study evaluated the effects of concurrent naloxone on the opioid agonist effects of buprenorphine, a mixed agonistantagonist marketed as an analgesic and under development as a treatment for drug abuse. In a residential laboratory seven non-physically-dependent opioid abuser volunteers received intramuscular buprenorphine (0.4 mg or 0.8 mg/70 kg) alone and in combination with naloxone (0.4 mg or 0.8 mg/70 kg) versus placebo. Buprenorphine produced dose-related opioid agonist effects on physiological and subjective measures. Concurrent naloxone attenuated the opioid agonist effects of buprenorphine. Thus, a combination product of buprenorphine and naloxone may have lower abuse liability than buprenorphine alone.     

Determinants of buprenorphine treatment for opioid dependence

This study assessed the social, demographic and clinical determinants of whether an opioid-dependent patient received buprenorphine versus an alternative therapy. A retrospective cohort analysis of opioid-dependent adults enrolled in Group Health Cooperative between January 1, 2006 and December 1, 2010 was performed. Increasing the number of physicians with DATA waivers in a region and living in a relatively-populated area increased the likelihood of being treated with buprenorphine, indicating that lack of access is a potential barrier. Comorbidity also appeared to be a factor in receipt of treatment, with the effect varying by diagnosis. Finally, patients with an insurance plan allowing health services to be sought from any provider, with increased cost sharing, were significantly more likely to receive buprenorphine, implying that patient demand is a factor. Programs integrating patient education, physician training, and support from addiction specialists would be likely facilitators of increasing access to this cost-effective treatment.     

胍丁胺抗阿片依赖研究进展

阿片成瘾,又称为阿片依赖,是一种慢性复发性脑疾病,可引起一系列严重的社会、经济和公共卫生问题。由于阿片依赖的神经生物学机制尚未阐明,目前仍缺乏有效的医学干预手段。研究阿片依赖的神经生物学机制、寻找有效的防复吸药物已成为阿片依赖研究领域的热点。胍丁胺是一种新发现的候选神经递质或调质,被认为是咪唑啉受体的内源性配体,本文主要以我们的研究工作为基础,对外源性胍丁胺的抗阿片依赖作用特点及其可能的作用机制加以综述。     

In vivo binding of naloxone to opioid receptors in morphine-dependent mice

In vivo binding assay of opioid receptors for naloxone was tested in morphine-dependent mice. The content of naloxone in the brain (whole brain minus cerebellum) and cerebellum was determined as the total binding and non-specific binding, respectively, 20 min after the intravenous injection of [3H]-naloxone. Acute treatment with 8 mg/kg of morphine sulfate markedly enhanced the non-specific binding of naloxone. In contrast, withdrawal for 6 hr after 72 hr of implantation of morphine decreased the non-specific binding of naloxone. The Scatchard analysis of the specific binding revealed two binding sites. The apparent low affinity Kd values of both morphine-tolerant and morphine-withdrawn mice were significantly decreased when compared to their respective controls. The apparent high affinity Kd and the high and low Bmax values were not altered by the morphine dependent-tolerant state.     

Effects of buprenorphine/naloxone in opioid-dependent humans

RATIONALE: Buprenorphine is a partial mu opioid agonist under development as a sublingual (SL) medication for opioid dependence treatment in the United States. Because buprenorphine may be abused, tablets combining buprenorphine with naloxone in a 4:1 ratio have been developed to reduce that risk. Low doses of injected buprenorphine/naloxone have been tested in opioid-dependent subjects, but higher doses (more than 2 mg of either medication) and direct comparisons to SL buprenorphine/naloxone have not been examined. OBJECTIVES: To assess and compare the effects of intramuscular (i.m.) versus SL buprenorphine/naloxone in opioid-dependent volunteers. METHODS: Opioid-dependent volunteers were maintained on 40 mg per day of oral hydromorphone while on a residential research ward. After safety testing in two pilot subjects, participants (n = 8) were tested with both i.m. and SL buprenorphine/naloxone (1/0.25, 2/0.5, 4/1, 8/2, 16/4 mg); i.m. hydromorphone (10 mg) and naloxone (0.25 mg); both i.m. and SL buprenorphine alone (8 mg); and placebo. Test sessions were twice per week; dosing was double-blind. RESULTS: Intramuscular buprenorphine/naloxone produced dose-related increases on indices of opioid antagonist effects. Effects were consistent with naloxone-precipitated withdrawal, and were short-lived. As withdrawal effects dissipated, euphoric opioid agonist effects from buprenorphine did not appear. Sublingual buprenorphine/naloxone produced neither opioid agonist nor antagonist effects. CONCLUSIONS: Intramuscular injection of buprenorphine/naloxone precipitates withdrawal in opioid dependent persons; therefore, the combination has a low abuse potential by the injection route in this population. Sublingual buprenorphine/naloxone by tablet is well tolerated in opioid dependent subjects, and shows neither adverse effects (i.e., precipitated withdrawal) nor a high abuse potential (i.e., opioid agonist effects).     

Effects of buprenorphine versus buprenorphine/naloxone tablets in non-dependent opioid abusers

Rationale: Buprenorphine is an opioid agonist-antagonist under development in the United States as a sublingual medication for treatment of opioid dependence. Buprenorphine may be abused; therefore, tablets combining buprenorphine with naloxone have been developed with the intent of reducing the abuse risk in people physically dependent upon opioids. The characteristics and abuse potential of buprenorphine and buprenorphine/naloxone tablets in non-dependent opioid abusers have not been determined. Non-parenteral abuse of opioids such as buprenorphine may be more likely in people who have less severe substance abuse disorders (e.g., are not physically dependent upon opioids). Objectives: To assess the abuse potential of sublingual buprenorphine and buprenorphine/naloxone tablets in non-dependent opioid abusers. Methods: Subjects (n=7) were tested with sublingual buprenorphine (4, 8, 16 mg), sublingual buprenorphine/naloxone (1/0.25, 2/0.5, 4/1, 8/2, 16/4 mg), as well as intramuscular hydromorphone as an opioid agonist control (2, 4 mg) and placebo in laboratory sessions conducted twice per week. Dosing was double-blind and double-dummy. Results: The higher doses of both buprenorphine and buprenorphine/naloxone produced similar opioid agonist-like effects. The onset of these effects was slowed, consistent with the sublingual route of administration, and the magnitude of effects was moderate. There was no evidence to suggest the addition of naloxone attenuated buprenorphine’s opioid agonist effects in this population when buprenorphine was delivered by the sublingual route. Conclusions: These results suggest that sublingual buprenorphine and buprenorphine/naloxone may both be abused by opioid users who are not physically dependent upon opioids. Received: 15 April 1999 / Final version: 11 September 1999     

丁丙诺啡药物依赖性评价

目的:调查评价阿片滥用人群中丁丙诺啡(buprenorphine,Bup)的药物依赖性及滥用潜力。方法:采用询问调查方法,对戒毒机构收治的阿片依赖者进行Bup使用情况、药物依赖性及滥用潜力的调查。被调查对象为使用Bup 3天以上,无精神障碍的阿片依赖者;调查内容包括药物滥用史,Bup一般使用情况和药物依赖性评价等。Bup的身体依赖性采用30项阿片戒断症状量表(OWS)评价。根据被调查对象先前出现过的Bup戒断症状经历(及严重程度)将各项症状/体征分为0-3分进行评价。对Bup的主观欣快效应采用视觉类比量表(VAS)评价。结果:共对1235例符合条件者进行了调查。被调查者初次使用Bup目的(多选择回答)以“戒毒目的使用”(占77.4％)和“治疗稽延性戒断症状”(占26.6％)为主。30项阿片戒断症状量表(OWS)平均分值介于0.2至1.3之间,除失眠、骨关节疼痛和烦躁不安平均分值分别为1.3、1.2和1.0外,其余症状均为1分以下,表明身体依赖性低。Bup“连续使用”,“间断使用”和“有时连续,有时间断使用”三种不同使用时间方式的OWS均分分别为0.9±0.9,0.4±0.5和0.7±0.4;ANOVA方差检验F值=70.846,P<0.05,差异具有极显著性。VAS测查结果表明,VAS均值为(27±24)mm,属“轻度”至“次中等”欣快程度;对Bup含服、注射两种不同使用途径的群体进     

Predictors of attrition with buprenorphine/naloxone treatment in opioid dependent youth

Background

In opioid dependent youth there is substantial attrition from medication-assisted treatment. If youth at risk for attrition can be identified at treatment entry or early in treatment, they can be targeted for interventions to help retain them in treatment.

Methods

Opioid dependent adolescents and young adults (n = 152), aged 15–21, were randomized to 12 weeks (BUP, n = 74) or 2 weeks of detoxification (DETOX, n = 78) with buprenorphine/naloxone (Bup/Nal), both in combination with 12 weeks of psychosocial treatment. Baseline and early treatment related predictors of treatment attrition were identified in each group using bivariate and multivariate logistic regression.

Results

In the DETOX group 36% left between weeks 2 and 4, at the end of the dose taper, while in the BUP group only 8% left by week 4. In the BUP group, early adherence to Bup/Nal, early opioid negative urines, use of any medications in the month prior to treatment entry, and lifetime non-heroin opioid use were associated with retention while prior 30-day hallucinogen use was associated with attrition. In the DETOX group, only use of sleep medications was associated with retention although not an independent predictor. A broad range of other pre-treatment characteristics was unrelated to attrition.

Conclusions

Prompt attention to those with early non-adherence to medication or an early opioid positive urine, markers available in the first 2 weeks of treatment, may improve treatment retention. Extended Bup/Nal treatment appeared effective in improving treatment retention for youth with opioid dependence across a wide range of demographics, and pre-treatment clinical characteristics.     

Single Dose of 24 Milligrams of Buprenorphine for Heroin Detoxification: An Open-label Study of Five Inpatients

Abstract

Previous studies indicate that buprenorphine has efficacy in medically supervised opioid withdrawal, but the optimal dosing for maximum tolerability and ease of administration remains undetermined. Five heroin-dependent individuals entered this open-label study of inpatient detoxification with a single 24mg dose of buprenorphine. The mean Clinical Opiate Withdrawal Scale (COWS) score prior to buprenorphine administration was 17.6 (SD = 3.36). COWS scores declined significantly thereafter. There was one episode of precipitated withdrawal that resolved within four hours. Use of ancillary medications was minimal. This study suggests that a single high dose of buprenorphine can be used safely and effectively for inpatient detoxification.