Simplified processing and rapid quantification of buprenorphine, norbuprenorphine, and their conjugated metabolites in human plasma using UPLC-MS/MS: Assessment of buprenorphine exposure during opioid use disorder treatment.

Opioid use disorder (OUD) is a chronic neurobehavioral ailment and is prevalent in pregnancy. OUD is commonly treated with methadone or buprenorphine (BUP). Pregnancy is known to alter the pharmacokinetics of drugs and may lead to changes in drug exposure and response. A simple, specific, and sensitive analytical method for measuring the parent drug and its metabolites is valuable for assessing the impact of pregnancy on drug exposure. A new liquid chromatography-tandem mass spectrometric method that utilized a simple protein precipitation procedure for sample preparation and four deuterated internal standards for quantification was developed and validated for BUP and its major metabolites (norbuprenorphine [NBUP], buprenorphine-glucuronide [BUP-G], and norbuprenorphine-glucuronide [NBUP-G]) in human plasma. The standard curve was linear over the concentration range of 0.05-100 ng/mL for BUP and NBUP, and 0.1-200 ng/mL for BUP-G and NBUP-G. Intra- and inter-day bias and precision were within ±15% of nominal values for all the analytes. Quality controls assessed at four levels showed high recovery consistently for all the analytes with minimal matrix effect. Adequate analyte stability was observed at various laboratory conditions tested. Overall, the developed method is simple, sensitive, accurate and reproducible, and was successfully applied for the quantification of BUP and its metabolites in plasma samples collected from pregnant women in a clinical study assessing BUP exposure during OUD treatment.

Quality Assessment of Expired Naloxone Products from First-Responders' Supplies.

Objective: Naloxone is an opioid receptor antagonist that reverses life-threatening effects of opioid overdose. Since the 1970s, naloxone products have been developed as injectable solutions, and more recently as nasal sprays. Naloxone products have saved many lives in emergency settings. These products are routinely carried by public safety first-responders including fire fighters (FF), law enforcement officers (LEO), and emergency medical services (EMS). Now, they are also distributed through community access programs to the public. While public safety medications are monitored, those publically distributed are not, so expired products can be possibly found on-hand in an emergency. This study analyzed the quality and stability of expired Naloxone HCl Solutions for Injection, to assess their remaining efficacies and potential risks. Methods: The samples were collected from EMS or law enforcement training supplies and expired returns, with expiration dates ranging from 1990 to 2018. Using standardized techniques, the remaining naloxone was quantified, and the main degradation products, nornaloxone (also known as noroxymorphone) and other possible species, were monitored and quantified systematically. Results: Most tested samples were found containing more than 90% of labeled naloxone, including those stored for nearly 30 years. The naloxone degradation was slow, but generally correlated with storage time length. There was no significant amount of degradation products detected across all samples. Nornaloxone was detected from some older samples, but all less than 1%. Therefore, although it is an opioid agonist, the risk caused by nornaloxone should be low. Conclusion: This quality assessment demonstrates that expired naloxone products may still meet USP standards, even after many years. Further pharmaceutical, clinical, and regulatory investigation should be conducted to confirm our findings, especially for new naloxone products with different formulations and routes of administration. Extending the shelf-life of naloxone products may have important financial and public health consequences in addressing future drug shortages and meeting the needs for this critical drug.

The preclinical discovery of lofexidine for the treatment of opiate addiction.

INTRODUCTION: Lofexidine is one therapeutic option used for treating the onslaught of sympathetic outflow that typically commences upon induction of opiate withdrawal. It was approved for opiate detoxification in the UK, most of EU, and a select few countries worldwide during the 1980s and the 90s. Within the US and Canada, however, it remains an experimental drug. AREAS COVERED: The following article highlights lacunae in extant knowledge about the molecular pharmacology of lofexidine. Furthermore, the article provides a brief discussion on the nature and shortcomings of clinical trials for this drug that have been conducted over the past 30 years across the world. It also provides a discussion of the market factors and regulatory considerations responsible for the rather limited use of lofexidine thus far. EXPERT OPINION: Many lessons can be learned from the 40-year-long development of lofexidine. Indeed, unless there is an urgent need to address an unmet and/or immediate health threat, preclinical development is dictated by pharmacoeconomic considerations. Lofexidine would likely have been excluded for further development in this day and age given the existence and value of clonidine as well as the lack of insurance coverage for opiate addiction. It should be noted, however, that although there have been many oversights in the past, current experimentation and clinical trials are beginning to address the mistakes made through the exploration of single enantiomers and controlled-release preparations.

Assessment of pharmacodynamic effects following oral administration of crushed morphine sulfate and naltrexone hydrochloride extended-release capsules compared with crushed morphine sulfate controlled-release tablets and placebo in nondependent recreational opioid users.

OBJECTIVES: To compare the pharmacodynamic effects, including self-reports of "drug liking" and "high," of crushed morphine sulfate and naltrexone hydrochloride extended-release capsules (MSN), crushed morphine sulfate controlled-release (CR) tablets, and placebo in an abuse potential study. DESIGN: Randomized, double-blind, placebo-controlled, three-way crossover study. SETTING: Single-center. SUBJECTS: Nondependent recreational opioid users. INTERVENTIONS: Orally administered crushed MSN (120-mg morphine sulfate and 4.8-mg naltrexone hydrochloride), crushed 120-mg morphine sulfate CR, and placebo. OUTCOME MEASURES: Subjective ratings (100-point visual analog scales) of positive drug effects (drug liking, high, good effects, take drug again, and overall drug liking), any effects, and negative effects (bad effects, feel sick, nausea, sleepy, and dizzy), along with pupillometry, pharmacokinetic (PK), and safety assessments. RESULTS: Crushed morphine sulfate CR significantly increased ratings of all positive subjective measures relative to placebo (P < 0.0001). Crushed MSN significantly decreased all positive subjective ratings compared with morphine sulfate CR (P ≤ 0.005), but significantly increased ratings compared with placebo (P < 0.03). Peak pupil diameter was significantly larger for MSN than morphine sulfate (P < 0.0001). PK analysis of morphine plasma concentrations indicated that Cmax was significantly lower and tmax significantly longer for crushed MSN compared with crushed morphine sulfate CR. Plasma concentrations of naltrexone and 6-ß-naltrexol were present following crushed MSN. CONCLUSIONS: This study demonstrated that when crushed and administered orally to nondependent recreational opioid users, MSN was associated with significantly lower scores on all positive subjective measures including drug liking and high, and significantly less pupil constriction compared with crushed morphine sulfate CR.

A retrospective assessment of the use of naltrexone implants for the treatment of problematic amphetamine use.

BACKGROUND: At present there is no registered effective pharmacotherapy for the treatment of problematic amphetamine use. OBJECTIVES: This study aims to examine self-reported abstinence from amphetamines following treatment with a sustained release naltrexone preparation in patients with self and clinically identified problems with amphetamine use and the relationship between naltrexone blood levels and abstinence from amphetamines. METHODS: Forty-four patients with problematic amphetamine use, who were treated with a naltrexone implant, completed an interview evaluating self-reported reduction in amphetamine use following treatment. Additional data were collected from the patients' clinical treatment files. RESULTS: Of the 44 subjects, 29 (65.9%) interviewed reported that following treatment they ceased using and maintained abstinence from amphetamines for at least 1 month. Of these patients, 14 (48.3%) were reportedly still abstinent at 6 months. Rates of abstinence were found to be 2.27 times higher (95% CI 1.38-3.74) in patients when blood naltrexone levels were above 2 ng/ml, with rates as high as 100% and 90.9% for ≥5 and ≥2 ng/ml, respectively, compared with 42.9% for 1-2 ng/ml and 38.9% low less than 1 ng/ml. CONCLUSIONS: Although this study has several limitations, the findings provide preliminary data in support of the use of implant naltrexone for the treatment of problematic amphetamine use and suggest that naltrexone levels above 2 ng/ml should be targeted for use in patients. SCIENTIFIC SIGNIFICANCE: Data supports the use of implant naltrexone, as a treatment for problematic amphetamine use, for which there is currently no registered pharmacotherapy. However, further research is required.

Utilization patterns of extended-release naltrexone for alcohol dependence.

OBJECTIVE: The purpose of this retrospective study was to evaluate health plan member utilization patterns of extended-release naltrexone (XR-NTX) and assess the cost of alcohol-related hospitalizations and medical and pharmacy costs. This is the first known study that examined post-XR-NTX therapy outcomes and costs. STUDY DESIGN: Retrospective analysis of claims data. METHODS: A sample of 48 members was identified with continuous pharmacy and medical benefit enrollment between July 1, 2006, and December 31, 2008, and a medical claim for reimbursement code J2315 (naltrexone for extended-release injectable suspension) with a date of service between July 1, 2007, and December 31, 2007. RESULTS: The average duration of XR-NTX therapy was 3 months. Among the 40% of patients who received 3 or more months of therapy, 58% had gaps in therapy. Post-XR-NTX therapy, alcohol-related hospitalization, medical, and pharmacy costs significantly decreased. CONCLUSION: Findings validate that abstinence from alcohol remains an issue after discontinuing therapy. Despite most patients being on therapy for less than 6 months, there were significant reductions in costs for alcohol-related hospitalizations, as well as total medical and total pharmacy costs.

Extended-release naltrexone for alcohol dependence: persistence and healthcare costs and utilization.

OBJECTIVE: Evaluate persistence with treatment, healthcare costs, and utilization in stably enrolled Aetna Behavioral Health members receiving extended-release naltrexone (XR-NTX) for alcohol use dependence compared with oral medications and psychosocial therapy only. STUDY DESIGN: Historical cohort study. METHODS: Aetna beneficiaries with stable enrollment (at least 6 months before and after index treatment) who initiated pharmacotherapy with XR-NTX (n = 211), disulfiram (n = 1043), oral naltrexone (n = 1408), acamprosate (n = 2479), or psychosocial therapy only (n = 6374) for alcohol use disorders between January 1, 2007, and December 31, 2008, were extracted and deidentified from Aetna's nationwide claims and utilization database. Survival analysis compared persistence with XR-NTX versus oral pharmacotherapies. Difference-in-differences analysis compared healthcare costs and utilization among patients receiving XR-NTX versus oral pharmacotherapies and psychosocial therapy only. Multivariate analyses controlled for demographics. RESULTS: Patients taking acamprosate and disulfiram were more likely to discontinue treatment than patients taking naltrexone, and patients given oral naltrexone were more likely to discontinue treatment than those given XR-NTX. Outpatient behavioral health treatment visits increased in all study groups. Nonpharmacy healthcare costs and utilization of inpatient and emergency services decreased in the XR-NTX group relative to other study groups. CONCLUSION: Patients receiving XR-NTX persisted with treatment longer than patients receiving oral alcohol use-disorder medications or psychosocial therapy only, and had decreased inpatient and emergency healthcare costs and utilization compared with those receiving other medications.

Assessment of dynamic neurotransmitter changes with bolus or infusion delivery of neuroreceptor ligands.

To describe the effect of endogenous dopamine on [11C]raclopride binding, we previously extended the conventional receptor ligand model to include dynamic changes in neurotransmitter concentration. Here, we apply the extended model in simulations of neurotransmitter competition studies using either bolus or bolus-plus-infusion (B/I) tracer delivery. The purpose of this study was (1) to develop an interpretation of the measured change in tracer binding in terms of underlying neurotransmitter changes, and (2) to determine tracer characteristics that maximize sensitivity to neurotransmitter release. A wide range of kinetic parameters was tested based on existing reversible positron emission tomography tracers. In simulations of bolus studies, the percent reduction in distribution volume (deltaV) caused by a neurotransmitter pulse was calculated. For B/I simulations, equilibrium was assumed, and the maximum percent reduction in tissue concentration (deltaC) after neurotransmitter release was calculated. Both deltaV and deltaC were strongly correlated with the integral of the neurotransmitter pulse. The values of deltaV and deltaC were highly dependent on the kinetic properties of the tracer in tissue, and deltaV could be characterized in terms of the tissue free tracer concentration. The value of deltaV was typically maximized for binding potentials of approximately 3 to 10, with deltaC being maximized at binding potentials of approximately 1 to 2. Both measures increased with faster tissue-to-blood clearance of tracer and lower nonspecific binding. These simulations provide a guideline for interpreting the results of neurotransmitter release studies and for selecting radiotracers and experimental design.

Determination of naloxone in human plasma by high-performance liquid chromatography with coulometric detection.

Naloxone, the analyte and the internal standard, sumatriptan, are extracted from plasma using solid-phase extraction columns. Chromatography and detection are performed using isocratic reversed-phase high-performance liquid chromatography (HPLC) with coulometric end-point detection. The standard curve was linear over the range 0-50 ng/ml of naloxone in plasma. The reproducibility, the coefficient of variation (C.V.) of the method over the range of the standard curve was 6.2-11.2%. The recovery averaged 90.4 +/- 8.9%. A plasma profile following i.v. administration of naloxone in one normal healthy volunteer is presented.