A retrospective chart review comparing tiagabine and benzodiazepines for the treatment of alcohol withdrawal

Although benzodiazepines are the standard of care in the treatment of alcohol withdrawal, several studies have suggested that anticonvulsants may be equally effective at alleviating alcohol withdrawal symptoms and may pose less of a risk of causing rebound of symptoms which could contribute to relapse. This report compares treatment outcomes for patients (N=13) treated for alcohol withdrawal with either the anticonvulsant tiagabine or the benzodiazepines oxazepam and lorazepam. The Clinical Institute Withdrawal Assessment for Alcohol-revised (CIWA-Ar) was utilized to gauge alcohol withdrawal symptoms over the course of the study. When possible, follow-up data was obtained on alcohol use post-treatment. Both benzodiazepines and tiagabine appeared to reduce CIWA-Ar scores at about the same magnitude. There was a trend for tiagabine patients to have less post-detoxification drinking (Fisher exact test, p = 0.12). The reduction in alcohol withdrawal symptoms and decreased tendency to relapse observed in patients treated with the anticonvulsant tiagabine suggests that a double-blind, placebo controlled trial may be warranted.     

Comparison of tincture of opium and methadone to control opioid withdrawal in a Thai treatment centre

AIMS: To evaluate the effectiveness of oral tincture of opium (TOP) and methadone to control opioid withdrawal in patients in northern Thailand. METHODS: Open label, parallel group study in an inpatient facility compared 15 former heroin users receiving methadone 5-20 mg 12 hourly with 15 former opium smokers receiving TOP (3.33-10 mg morphine equivalents 12 hourly). At 0, 1, 3 and 8 h, blood, withdrawal scores and subjective opioid effects were collected. RESULTS: There was a reciprocal association between withdrawal scores/direct subjective opioid effects and plasma (R)-methadone, but not plasma morphine, concentrations. Withdrawal scores at the time of dosing were higher in the TOP patients (9.1 +/- 3) than in the methadone patients (4.5 +/- 4.6) and in the TOP patients were significantly (P = 0.001) attenuated at 3 and 8 h. CONCLUSIONS: At the doses used, TOP was inferior to methadone in suppressing withdrawal. It could prove to be a cost effective and valuable drug, but only after dose size and frequency are further investigated.     

Use of methadone for prevention of opioid withdrawal in critically ill children

Background

Opioids are commonly administered to critically ill children for analgesia and sedation, but many patients experience opioid withdrawal upon discontinuation. The authors’ institution developed a protocol for using methadone to prevent opioid withdrawal in children who have received morphine by continuous IV infusion for 5 days or longer in the pediatric intensive care unit (PICU).

Objectives

The primary objectives were to determine if opioids were tapered according to the protocol and to determine the conversion ratio for IV morphine to oral methadone that was used. Secondary objectives were to describe the methadone dosage used and the clinical outcomes, to evaluate adjustments to methadone dosing, and to report the incidence of adverse effects.

Methods

A retrospective analysis of charts was conducted for pediatric patients who had received morphine by continuous IV infusion for 5 days or longer followed by methadone in the PICU between May 2008 and August 2009. Validated scoring systems (the Withdrawal Assessment Tool and the State Behavioral Scale) were used to assess symptoms of withdrawal and degree of sedation, respectively.

Results

Forty-three patients were included in the study, with median age of 8 months (range 0.25–201 months). For 31 patients (72%), the protocol was not used, and there were no patients for whom the protocol was followed to completion. The median duration of weaning was 10 days (range 0–91 days). The conversion ratio for IV morphine to oral methadone was 1:0.78 for anticipated 5-day weaning and 1:0.98 for anticipated 10-day weaning. During the first 10 days of weaning, 18 patients (42%) experienced withdrawal symptoms. The methadone dose was increased for 11 (26%) of the 43 patients. Patients were sedated for a median of 1 day (range 0–9 days), were comfortable for a median of 6.5 days (range 1–64 days), and were agitated for a median of 2.5 days (range 0–23 days). Naloxone was required for 2 patients.

Conclusions

The institution’s methadone protocol was not followed consistently during the study period, and practices for transitioning from morphine by continuous IV infusion to methadone with tapering were also inconsistent. Further studies are needed to determine the optimal conversion ratio for morphine to methadone and the optimal tapering regimen to minimize withdrawal symptoms and adverse events.     

Efficacy of buspirone in the treatment of opioid withdrawal

In an attempt to develop a new opiate detoxification approach, the authors assessed the efficacy of buspirone in the treatment of acute heroin withdrawal. Buspirone, a drug interacting with the serotonergic system, was selected because there is evidence that a decrease in serotonergic neurotransmission may be involved in opiate withdrawal symptoms. Twenty-nine hospitalized heroin addicts were randomized to 4 groups: (1) placebo; (2) methadone; (3) buspirone 30 mg daily; (4) buspirone 45 mg daily. The double-blind trial started in all patients with a 5-day methadone stabilization period ending with a 30-mg dose. This was followed from days 6 through 12 by placebo in group 1 and by a methadone taper in group 2. Because of its delayed action, buspirone was started on day 1 in groups 3 and 4 and was continued, after methadone discontinuation, through day 12. On day 13, drugs and placebo were discontinued and patients were observed through day 14. Withdrawal symptoms were assessed with the "Subjective Opiate Withdrawal Scale" (SOWS) and the "Objective Opiate Withdrawal Scale" (OOWS). The SOWS and OOWS scores were significantly higher in the placebo group than in the methadone, buspirone 30 mg, and buspirone 45 mg groups. There were no significant differences in SOWS or OOWS scores when the methadone group was compared with each of the two buspirone groups or when the two buspirone groups were compared with one another. In conclusion, buspirone, a nonopiate drug with no abuse potential, a safe side effect profile and no withdrawal symptoms, at doses of 30 and 45 mg, was as effective as a methadone taper in alleviating the withdrawal symptoms of heroin addicts stabilized for 5 days with, and then withdrawn from, methadone. The use of buspirone could be particularly helpful in outpatient settings where the duration of the methadone taper recommended for detoxification can be lengthy.     

ALDH5A1 variability in opioid dependent patients could influence response to methadone treatment

Methadone maintenance treatment is the most widely-used therapy in opioid dependence, but some patients relapse or drop out from treatment. We genotyped a genetic variant in the succinic semialdehyde dehydrogenase enzyme gene, ALDH5A1, and found that subjects carrying the T variant allele have a higher risk to be nonresponders to methadone treatment (OR=3.16; 95% CI [1.48–6.73], P=0.0024). This could be due to a reduction in the ALDH5A1 enzyme activity, that would increase endogenous gamma-hydroxbutyric acid (GHB) and gamma-aminobutyric acid (GABA) levels and therefore, inducing symptoms such as sedation and impaired pschomotor performance. These neuropsychological effects related with the reduction in enzyme activity could be responsible for a higher propensity to relapse in these genetically predisposed patients.     

Survival study of opioid addicts in relation to its adherence to methadone maintenance treatment

OBJECTIVES: To study the putative role of methadone maintenance treatment in the improvement of life expectancy of opioid addicts. DESIGN: Retrospective longitudinal study. Participants: All 1487 patients receiving methadone maintenance treatment in Alicante between June 1990 and December 1997. STATISTICAL ANALYSIS: Mortality rates were studied using Kaplan-Meier survival curves. Protection or risk factors were analyzed using Cox's proportional hazards model. RESULTS: Mortality rates decreased from 87/1000 in 1991 to 17/1000 in 1997. The following factors influenced mortality: HIV infection [Hazard Ratio (HR)=7, 95% confidence interval (CI)=4-12]; current methadone status (HR=3.2, 95%CI=1.5-7.1) and MMT retention (retained vs. drop-out, HR=0.5, 95%CI=0.2-1.1; re-enrolled vs. drop-out, HR=0.3, 95%CI=0.2-0.5). CONCLUSION: Expediting entry and re-enrolling in methadone maintenance treatment improves survival.     

Characteristics of methadone maintenance treatment patients prescribed opioid analgesics

ABSTRACT

Background: Opioid analgesic use and disorders have dramatically increased among the general American population and those receiving methadone maintenance treatment (MMT). Most research among MMT patients focuses on opioid analgesics misuse or disorders; few studies focus on MMT patients prescribed opioid analgesics. We describe demographic, clinical, and substance use characteristics of MMT patients prescribed opioid analgesics and compare them with MMT patients not prescribed opioid analgesics. Methods: We conducted a cross-sectional secondary data analysis using screening interviews from a parent study. From 2012 to 2015, we recruited adults from 3 MMT Bronx clinics. Questionnaire data included patterns of opioid analgesic use, substance use, comorbid illnesses, and demographic characteristics. Our main dependent variable was patients' report of currently taking prescribed opioid analgesics. To compare characteristics between MMT patients prescribed and not prescribed opioid analgesics, we conducted chi-square tests, t tests, and Mann-Whitney U tests. Results: Of 611 MMT patients, most reported chronic pain (62.0%), hepatitis C virus (HCV) infection (52.1%), and current use of illicit substances (64.2%). Of the 29.8% who reported currently taking prescribed opioid analgesics, most misused their opioid analgesics (57.5%). Patients prescribed (versus not prescribed) opioid analgesics were more likely to report human immunodeficiency virus (HIV) infection (adjusted odds ratio [aOR] = 1.6, 95% confidence interval [CI]: 1.1–2.3) and chronic pain (aOR = 7.6, 95% CI: 4.6–12.6). Conclusion: Among MMT patients primarily in 3 Bronx clinics, nearly one third reported taking prescribed opioid analgesics. Compared with patients not prescribed opioid analgesics, those prescribed opioid analgesics were more likely to report chronic pain and HIV infection. However, between these patients, there was no difference in illicit substance use. These findings highlight the complexity of addressing chronic pain in MMT patients.     

A case for addressing cigarette use in methadone and other opioid treatment programs

Most persons attending drug treatment smoke cigarettes. They will eventually experience predictable, but devastatingly high, tobacco-related mortality. Recent studies indicate that many clients are ready to quit smoking and that quitting does not threaten progress made in treatment. Methadone and other opioid treatment providers are in an excellent position to address tobacco use among their clients. The present paper describes the prevalence of smoking among methadone clients, reviews promising interventions, and describes how programs can implement a systematic approach to smoking cessation that includes creating a cue system for identifying smokers, providing brief on-site intervention, and arranging follow-up or more intensive treatment.     

Pharmacokinetic-pharmacodynamic modeling of mood and withdrawal symptoms in relation to plasma concentrations of methadone in patients undergoing methadone maintenance treatment

ABSTRACT: The aims of the present study were to characterize the relationship between plasma racemic methadone and its enantiomers' concentrations with respect to their pharmacodynamic effects and to investigate the influence of potential covariates on the pharmacodynamic parameters in patients on methadone maintenance treatment (MMT).Eighty-eight regular subjects at the Sheffield Care Trust Substance Misuse Services were studied. Samples of blood and urine were collected before the daily dose of methadone. Blood samples were taken up to 5 hours after dose. Total plasma concentrations of (RS)-methadone and total and unbound plasma concentrations of both enantiomers were measured by liquid chromatography-mass spectrometry. The Total Mood Disturbance Score (TMDS), the Objective Opioid Withdrawal Scale (OOWS), and the Subjective Opioid Withdrawal Scale (SOWS) were used as measures of mood and withdrawal. Population pharmacokinetic/pharmacodynamic analysis and subsequent multiple regression analysis were used to determine the factors influencing the pharmacodynamic effects of methadone.Significant decreases (P ≤ 0.04) were observed in the scores for the TMDS, SOWS, and OOWS for 5 hours after methadone dosage. The TMDS had returned to baseline by 10 hours after dose (P = 0.98), at which time the SOWS remained significantly below baseline (P = 0.001). Multiple regression analysis revealed that 33% of the overall variation in unbound (R)-methadone EC50 was explained by 3 variables, namely CYP3A activity (9%), age (16%), and sex (8%). Age also accounted for 8% and 9% of the variation in total (rac)- and (R)-methadone EC50.The present study has confirmed that the duration of mood change in the present study was shorter than the effect of methadone in stabilizing withdrawal symptoms. Thus, it is likely that a once-daily dose of methadone, albeit effective for preventing withdrawal, may not be sufficient to improve mood in some patients. Finally, it was established that CYP3A activity, years of dependent use, sex, and age are major determinants of methadone EC50 with respect to TMDS.     

A brief history of methadone in the treatment of opioid dependence: a personal perspective.

Starting at the latter part of the nineteenth century and through the early twentieth century, events are reviewed to provide a sense of the climate and setting in which early methadone research was conducted. The discovery of methadone by the Germans in the later stages of World War II is described. At that time, methadone was not recognized to be a narcotic analgesic. The first report of the properties of methadone published in the United States in 1947 is summarized, and its early use in the treatment of the opioid abstinence syndrome is noted. However, the utility of methadone as a maintenance drug was not recognized until 14 years later. Despite strong resistance from the U.S. Bureau of Narcotics, research progressed from the recognition of the unique properties of methadone to substantial clinical application. Finally, methadone is placed in a current context describing a second wave of acceptance based not solely on the reduction of crime but on the prevention of the spread of AIDS.     

Use of drug combinations in treatment of opioid withdrawal.

During the last 10 years new approaches for rapid opioid detoxification have included drug combinations such as clonidine and naltrexone to speed and ease the transition from opioid agonist to antagonist maintenance. Other drug combinations include naloxone with midazolam or methohexitone for inpatients, but rapid outpatient methods are more desirable. Clonidine combined with naltrexone enables abrupt opioid withdrawal in 3-5 days in an outpatient/day setting. This approach can be further improved by transition to the partial agonist buprenorphine from either heroin or methadone followed by a 1 day detoxification using naltrexone precipitated withdrawal, ameliorated by clonidine.     

Antagonist treatment of opioid withdrawal translational low dose approach

Although antagonist drugs are receiving increasing attention in the treatment of opioid withdrawal, the mechanisms of interaction of opiate agonists and antagonists remain largely to be investigated. We focused on the effects of very low quantities of opiate antagonists, following the clinical indication of their potential utility in detoxification. Upon reviewing the evidence on the administration of small doses of naloxone and naltrexone in the presence of agonist drugs, the effects of low-dose naltrexone during opiate administration and withdrawal are described. The application of a translational methodology allowed completing the clinical design with behavioral and cellular information obtained from a specifically developed animal model. The initial results indicate that low doses of naltrexone may help reducing the manifestation of opioid withdrawal, offer suggestions for further investigations and confirm the utility of a translational research approach to the clinical neurobiology of drug addiction.     

新生儿戒断综合征的临床特点及救治体会

目的:探讨新生儿戒断综合征的临床特点及治疗措施。方法:对连云港市妇女儿童医院7例新生儿戒断综合征进行分析。结果:7例新生儿戒断综合征,其中早产儿3例,足月儿4例。新生儿窒息2例,宫内窘迫行剖宫产2例,先天性梅毒1例。结论:母亲吸毒对新生儿危害极大,全社会应共同关注毒品危害,保障妇女和儿童的生命健康。