Does high-dose buprenorphine cause respiratory depression?: possible mechanisms and therapeutic consequences

Buprenorphine is an opioid agonist-antagonist with a 'ceiling effect' for respiratory depression. Compared with methadone, its unique pharmacology offers practical advantages and enhanced safety when prescribed as recommended and supervised by a physician. Buprenorphine has been approved in several countries as an efficient and safe maintenance therapy for heroin addiction. Its use resulted in a salutary effect with a reduction in heroin overdose-related deaths in countries that implemented office-based buprenorphine maintenance. In France, however, where high-dose buprenorphine has been marketed since 1996, several cases of asphyxic deaths were reported among addicts treated with buprenorphine. Death resulted from buprenorphine intravenous misuse or concomitant sedative drug ingestion, such as benzodiazepines. In these situations of abuse, misuse, or in association with elevated doses of psychotropic drugs, buprenorphine may cause severe respiratory depression. Unlike other opiates, the respiratory effects from buprenorphine are not responsive to naloxone. However, the exact mechanism of buprenorphine-induced effects on ventilation is still unknown. The role of norbuprenorphine, the main N-dealkylated buprenorphine metabolite with potent respiratory depressor activity, also remains unclear. Experimental studies investigating the respiratory effects of combinations of high doses of buprenorphine and benzodiazepines suggested that this drug-drug interaction may result from a pharmacodynamic interaction. A pharmacokinetic interaction between buprenorphine and flunitrazepam is also considered. As there are many questions regarding the possible dangers of death or respiratory depression associated with buprenorphine use, we aimed to present a comprehensive critical review of the published clinical and experimental studies on buprenorphine respiratory effects.     

Dysphoric mania induced by high-dose mirtazapine: a case for 'norepinephrine syndrome'?

The antidepressant mirtazapine antagonizes central presynaptic alpha2-adrenergic auto- and heteroreceptors resulting in increased central norepinephrine and serotonin activity. Histamine H2 receptors are also antagonized, as are postsynaptic serotonin 5-HT2 and 5-HT3 receptors, leading to serotonergic activity primarily via 5-HT1A receptors. Based on the case report of a patient who developed mania with higher than recommended dosage of mirtazapine, we review the literature on the atypical nature of manic symptoms with mirtazapine. Eight subjects, including those in our study, were identified as having developed mirtazapine-induced mania with atypical features, consisting of dysphoria, irritability, insomnia, psychomotor agitation and abnormal gait. Predisposing features may have included the presence of underlying brain dysfunction and certain selective serotonin reuptake inhibitor-mirtazapine combinations. Dysphoric mania with atypical features may be induced by mirtazapine, providing support for a common hypothesis such as 'central norepinephrine hyperactivity' as the basis for development of mania with mirtazapine.     

Is there a role for adjuvant high-dose interferon-alpha-2b in the management of melanoma?

The knowledge that melanoma is susceptible to attack by the host's immune system has resulted in the testing of a variety of immunotherapies. Interferon-alpha-2b, which has several anti-tumour mechanisms including an antiproliferative effect, an anti-angiogenesis effect, the enhancement of natural-killer cell activity and the upregulation of tumour antigen presentation, has shown tremendous potential. Early trials using low-dose and intermediate-dose regimens demonstrated no benefit to survival. However, the Eastern Cooperative Oncology Group trial EST 1684, showed that a high-dose regimen involving an induction phase of intravenous interferon-alpha-2b 20 MU/m(2) 5 days a week for 4 weeks, followed by a maintenance phase of subcutaneous 10 MU/m(2) 3 days a week for the remainder of a year, led to significant improvements in both disease-free and overall survival compared with observation. On the basis of these results, the US FDA approved high-dose interferon-alpha-2b for the post-surgical adjuvant therapy of high-risk melanoma. Unfortunately, the results of subsequent trials involving high-dose interferon-alpha-2b have not been as clear, and its role in the adjuvant treatment of melanoma remains controversial. Concerns remain regarding the design and interpretation of the clinical trials, the cost and toxicity of treatment, and the appropriate selection of patients who should be treated. This article reviews the existing data and attempt to address the arguments for and against a role for adjuvant high-dose interferon-alpha-2b in the management of melanoma.     

Does high-dose benzodiazepine abuse really produce liver toxicity? Results from a series of 201 benzodiazepine monoabusers

Background: Several side-effects related to prolonged benzodiazepines (BZD) use have been reported. Given the primary role of liver in BZD metabolism, toxicity related to prolonged high-dose BZD use could be conceivable. No data are available on the long-term impact of high-dose BZD use on liver.

Research design and methods: A total of 201 BZD mono-abusers admitted to an Addiction Unit for detoxification were evaluated. Liver enzymes were evaluated at admission, before starting any treatment. An elevation of more than five times the upper limit of normal range (ULN) in serum ALT or conjugated bilirubin, or a combined elevation of AST, alkaline phosphatase and total bilirubin, one of which exceeding >2 the ULN, was considered diagnostic for drug-induced liver injury.

Results: None of the evaluated subjects showed significant alterations of liver enzymes. Those with the highest transaminase levels were showing high body mass index. Twenty patients (10%) showed elevated gamma-glutamyl-transferase. No alteration of alkaline phosphatase, nor bilirubin was found in any patient. The average dosage of BZD was 307 mg of diazepam-equivalents for 7 years.

Conclusions: Present data suggest that prolonged use of high-dose BZD, although very dangerous for several reasons, does not seem to produce a significant drug-induced liver injury.     

Computational fluid dynamics (CFD) assisted performance evaluation of the Twincer™ disposable high-dose dry powder inhaler

Objectives To use computational fluid dynamics (CFD) for evaluating and understanding the performance of the high‐dose disposable Twincer? dry powder inhaler, as well as to learn the effect of design modifications on dose entrainment, powder dispersion and retention behaviour. Methods Comparison of predicted flow and particle behaviour from CFD computations with experimental data obtained with cascade impactor and laser diffraction analysis. Key findings Inhaler resistance, flow split, particle trajectories and particle residence times can well be predicted with CFD for a multiple classifier based inhaler like the Twincer?. CFD computations showed that the flow split of the Twincer? is independent of the pressure drop across the inhaler and that the total flow rate can be decreased without affecting the dispersion efficacy or retention behaviour. They also showed that classifier symmetry can be improved by reducing the resistance of one of the classifier bypass channels, which for the current concept does not contribute to the swirl in the classifier chamber. Conclusions CFD is a highly valuable tool for development and optimisation of dry powder inhalers. CFD can assist adapting the inhaler design to specific physico‐chemical properties of the drug formulation with respect to dispersion and retention behaviour.     

The NK₁ receptor antagonist aprepitant does not alter the pharmacokinetics of high-dose melphalan chemotherapy in patients with multiple myeloma

AIMS

The objective of this investigation was to assess the effect of aprepitant on the pharmacokinetics of high-dose melphalan used as conditioning therapy before blood stem cell transplantation in multiple myeloma.

METHODS

Aprepitant (125 mg) or placebo was administered 1 h before melphalan therapy (1 h infusion of 100 mg m⁻²). Eleven plasma samples were obtained over 8 h and melphalan was quantified using an LC/MS/MS method. Standard pharmacokinetic parameters were calculated and nonparametric testing was applied to assess the differences between aprepitant and placebo treatment.

RESULTS

Twenty patients received placebo and 10 patients aprepitant treatment. There were no differences observed for C_max at the end of melphalan infusion (placebo 3431 ± 608 ng ml⁻¹vs. aprepitant 3269 ± 660 ng ml⁻¹). In addition, AUC and terminal elimination half-life were not changed by aprepitant. Total clearance of melphalan was 304 ± 58 ml min⁻¹ m⁻² (placebo) which was not influenced by aprepitant (288 ± 78 ml min⁻¹ m⁻²).

CONCLUSIONS

The administration of the NK₁ receptor antagonist aprepitant 1 h before a high-dose chemotherapy does not influence the exposure and the elimination of melphalan. Therefore, oral administration of 125 mg aprepitant 1 h before melphalan infusion does not alter the disposition of intravenously administered melphalan.     

O-Mel-Inib: A Cancéro-pôle Nord-Ouest multicenter phase II trial of high-dose Imatinib mesylate in metastatic uveal melanoma

Summary   Background: Nowadays, there is no consensual and effective treatment in metastatic uveal melanoma (MUM). Numerous preclinical data (for example, 75% of MUM express c-kit) suggest that imatinib mesylate (IM) may be a potential treatment of UMM. Methods: The primary objective of this phase II trial was to determine the non-progression rate at 3 months for patients receiving IM at dose of 400 mg twice per day orally. The study was based on a Simon’s optimal design, which allows entry a total of 29 patients, if at least two non-progressions among ten first patients were observed. Result: Thirteen patients including ten assessable patients were enrolled in 12 months. No objective response and only one stable disease with duration of 5 months were noted. Five and one out of 13 enrolled patients experienced grade 3 and grade 4 toxicities, respectively. The most common severe adverse events were abdominal pain. The overall survival was 10.8 months. Conclusions: Despite promising preclinical data, IM is an inactive single agent in MUM. This phase II clinical trial has been stopped at the first step. Presented in part at 44th ASCO Annual Meeting Chicago, Illinois May 30–June 03, 2008     

Factors associated with adverse reactions to cocaine among a sample of long-term, high-dose users in São Paulo, Brazil

This cross-sectional survey investigates the frequency of adverse cocaine reactions and associated factors among regular cocaine misusers. A sample of 332 cocaine misusers from a range of treatment and nontreatment settings in S?o Paulo, Brazil, were interviewed using a questionnaire that includes the Severity of Dependence Scale (SDS), the General Health Questionnaire (GHQ-28), the CAGE, and an eight-item questionnaire investigating the frequency of specific adverse cocaine reactions. The most commonly described reactions were hot flushes (84%), uncontrollable shaking (76%), and feeling ill (75%). The most severe symptoms and least common were convulsions or fits (18%) and passing out (21%). Frequency of adverse reactions to cocaine was positively associated with out-of-treatment status, severity of cocaine dependence, ever having injected cocaine, using tranquilisers with cocaine, and GHQ score. Adverse reactions to cocaine are common among regular cocaine users. Some of the adverse effects, especially those on the heart and central nervous system, are potentially fatal. Preventive strategies should be developed to reduce the risk of adverse cocaine reactions. The findings are discussed in relation to the type of interventions that might be developed and lines of future research.     

Reduced mitochondrial coenzyme Q10 levels in HepG2 cells treated with high-dose simvastatin: a possible role in statin-induced hepatotoxicity?

Lowering of low-density lipoprotein cholesterol is well achieved by 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins). Statins inhibit the conversion of HMG-CoA to mevalonate, a precursor for cholesterol and coenzyme Q10 (CoQ10). In HepG2 cells, simvastatin decreased mitochondrial CoQ10 levels, and at higher concentrations was associated with a moderately higher degree of cell death, increased DNA oxidative damage and a reduction in ATP synthesis. Supplementation of CoQ10, reduced cell death and DNA oxidative stress, and increased ATP synthesis. It is suggested that CoQ10 deficiency plays an important role in statin-induced hepatopathy, and that CoQ10 supplementation protects HepG2 cells from this complication.     

Pharmacokinetics of high-dose buprenorphine following single administration of sublingual tablet formulations in opioid naïve healthy male volunteers under a naltrexone block

Sublingual buprenorphine formulations have been developed as treatments for opioid dependence. In three studies, opioid na?ve healthy male subjects received Subutex tablets (buprenorphine 2 and 8 mg [N=27] or 12 and 16 mg [N=27]) or Suboxone (two formulations) tablets (buprenorphine 8 mg/naloxone 2 mg [N=36]) sublingually, under a naltrexone block for assessment of buprenorphine pharmacokinetics and tablet disintegration times. Plasma buprenorphine was quantified up to 72 h post-dose using a sensitive LC-MS/MS assay. Mean Cmax values ranged from 1.6 to 6.4 ng/ml and tmax from 0.5 to 3 h. Concentrations declined bi-exponentially and fluctuations after a meal suggested enterohepatic recirculation of buprenorphine. The terminal half-life was approximately 26 h (range 9-69). Cmax and AUC appeared to increase in proportion to Subutex dose over 8-16 mg. The Suboxone formulations were bioequivalent. The least squares mean (90% CI) treatment ratio for Cmax was 1.00 (0.92-1.10) and AUC was 1.00 (0.95-1.06). Median times of disintegration were similar for all doses and formulations (range 6-12 min). Sublingual buprenorphine, up to 40 times the 400 microg analgesic dose, was well tolerated in these opioid na?ve subjects, as administration of naltrexone 50-150 mg was sufficient to attenuate anticipated adverse effects in this population of subjects.     

Cost–utility analysis of reslizumab for patients with severe eosinophilic asthma inadequately controlled with high-dose inhaled corticosteroids and long-acting β2-agonists in South Korea

Objectives: We aimed to assess the cost-utility of reslizumab for patients with severe eosinophilic asthma uncontrolled with high-dose inhaled corticosteroids and long-acting β₂-agonists (ICS/LABAs) in Korea.

Methods: A Markov model with limited societal perspective was used to compare the costs and quality-adjusted life years (QALYs) of reslizumab add-on therapy with standard-of-care (high-dose ICS/LABA) and standard-of-care alone. The model adopted a 4?week cycle with the following six health states over a lifetime (60?years): controlled asthma, uncontrolled asthma, moderate exacerbation, severe exacerbation, all-cause death and asthma-related death. The population comprised adult patients (age ≥18?years) with severe eosinophilic asthma (eosinophils ≥400 cells/μL) at Global Initiative for Asthma (GINA) step 4 or 5 who had experienced at least three exacerbations in the preceding year. Model inputs were sourced from individual patient-level data from two 52?week randomized controlled trials of reslizumab (NCT01287039, NCT01285323). The model included discontinuation rules where patients uncontrolled with reslizumab add-on therapy were transitioned to the standard-of-care arm. Costs and QALYs were annually discounted at 5%. Deterministic and probabilistic sensitivity analyses were performed.

Results: Reslizumab add-on therapy was associated with increased cost (US$119,394) and improved QALYs (5.17) compared with standard-of-care alone, resulting in an incremental cost-effectiveness ratio of US$23,081 per QALY gained. Body weight, time horizon and discount rate were influential factors in the model.

Conclusions: The addition of reslizumab to high-dose ICS/LABA was cost-effective in Korean patients with severe eosinophilic asthma uncontrolled with high-dose ICS/LABA, based on the threshold of 1 gross domestic product in Korea.