Impaired psychomotor function and plasma methadone and levo-alpha-acetylmethadol (LAAM) concentrations in opioid-substitution patients.

Tolerance to the psychomotor impairing effects of opioid drugs is expected to develop with repeated dosing, but may be incomplete. The relationship between plasma opioid concentration and psychomotor function in opioid-dependent patients was examined to determine whether impairment was more likely at the time of highest plasma drug concentration. Sixteen patients participating in a cross-over trial comparing methadone and LAAM completed a tracking task (OSPAT) 11 times over the dosing-interval for methadone (24-hrs) and LAAM (48-hrs). Venous blood was collected for the quantification of plasma (R)-(-)-methadone, LAAM, and nor-LAAM concentrations. The Digit Symbol Substitution Test (DSST) and Trail-Making Test were administered at the time of peak plasma concentration. Ten healthy controls (HCs) also participated. OSPAT scores (obtained for 15 patients) fluctuated significantly across the dosing-interval for both drugs and were lower in patients than HCs at the times of peak concentrations of (R)-(-)-methadone (1 hr: (mean difference; 95% CI) (2.13; 0.18-4.08); 2 hrs: (2.38; 0.48-4.28) postdosing) and LAAM (2 hrs: (1.81; 0.09-3.53), and 4 hrs (1.90: 0.9-3.71) postdosing). Within-participant analysis of the peak-change from baseline for OSPAT scores found that 10 of the 15 patients could be categorized as impaired on methadone and 9 on LAAM. No HCs were impaired. Patients performed worse on the DSST and Trails-A than HCs, but not on Trails-B. Results suggest that some patients receiving opioids long term may exhibit impairment at the time of highest plasma drug concentration. These patients should be made aware that their ability to undertake complex tasks may be affected. (PsycINFO Database Record

[Accidental levomethadone intoxication in a palliative patient]. / Akzidentielle Levomethadonintoxikation bei einer Palliativpatientin.

Levomethadone is a strong opioid which is used rarely in the treatment of special pain syndromes in Germany. A main field for the usage of Levomethadone, which has be applied as a oral fluid, is the opioid replacement therapy of heroin-addicts. Due to the long plasma half life and its high inter-individual variability, the application implies a risk of cumulation leading to an overdosage. It is not recommended to use a fixed equianalgesic formula for the dosage conversion from other opioids. The conversion starts with a low start dose, an individual titration follows. In this case-report, the difficulty of cumulation, inaccurate drug dispensary and the characteristic of dosage calculation of levomethadone is discussed.

Effect of PTSD diagnosis and contingency management procedures on cocaine use in dually cocaine- and opioid-dependent individuals maintained on LAAM: a retrospective analysis.

This randomized clinical trial retrospectively examined the effect of post-traumatic stress disorder (PTSD) and contingency management (CM) on cocaine use in opioid and cocaine dependent individuals maintained on high or low-dose LAAM randomly assigned to CM or a yoked-control condition. Cocaine-positive urines decreased more rapidly over time in those without PTSD versus those with PTSD in the noncontingency condition. In participants with PTSD, CM resulted in fewer cocaine-positive urines compared to the noncontingent condition. This suggests that CM may help improve the potentially worse outcomes in opioid- and cocaine-dependent individuals with PTSD compared to those without PTSD. (Am J Addict 2010;00:1-9).

Longitudinal effects of LAAM and methadone maintenance on heroin addict behavior.

Levo-alpha-acetylmethadol maintenance (LAAM) was compared to methadone maintenance (MM) on the behavioral performance of 315 heroin addicts before, during, and after 12 months of fully subsidized treatment. Assessments of drug use, criminal behavior, HIV risk behaviors, and employment and residential status were obtained at treatment intake and at 6, 12, and 18 months after admission. Treatment retention and in-treatment suppression of heroin use were significantly better for the LAAM group than for the MM group. Improvements were also noted during treatment in criminal behavior, criminal justice involvement, and employment status, and there were reductions in injection HIV risk and number of sexual partners. Most significant effects were primarily related to active participation in maintenance treatment. Under subsidized treatment, retention rates were two to four times that of similar clients in local community programs during the same period. LAAM was a useful and a potentially important addition to treatment options for opiate addiction, conferring greater retention and opiate suppression benefits. Its removal from application provides a historical lesson concerning the introduction of new medications into addiction health services.

Sex and opioid maintenance dose influence response to naloxone in opioid-dependent humans: a retrospective analysis.

Pooled self-report and physiological data from 32 male and 15 female methadone or levo-alpha-acetyl methadol (LAAM) maintained volunteers were retrospectively analyzed for individual differences in response to naloxone (0.15 mg/70 kg, IM) and placebo at 20 and 40 min post-injection. Males and females were each divided by the median splitmethadone maintenance dose (MMD, in mg/kg body weight) into high and low MMD groups and MMD was used as a factor in the analyses, along with sex, drug, and time post-drug. Females in the low but not high, MMD group showed naloxone-induced increases in ratings on the Antagonist and Mixed-Action sub-scales of the Adjective Rating Scale, and the Lysergic acid diethyl amine (LSD) sub-scale of the Addiction Research Center Inventory at 20 min post-injection. Males in the high MMD group showed significant naloxone-induced increases in scores of these measures at both post-injection time-points. In addition, low MMD subjects showed more short-lived naloxone-induced increases on Visual Analogue Scale (VAS) Bad and Any drug effects ratings than high MMD subjects. These results suggest that those on a lower MMD, especially women, experience a more intense, but short-lived, response to naloxone, whereas those on a higher MMD experience a more modest, but longer-lasting effect.

QT-interval effects of methadone, levomethadyl, and buprenorphine in a randomized trial.

BACKGROUND: Levomethadyl acetate, methadone hydrochloride, and buprenorphine hydrochloride are equally effective treatments for opioid dependence. Each blocks the human ether-a-go-go-related gene (hERG)-associated channel in vitro and represents a risk for QT prolongation. To compare the effects of 3 known hERG-associated channel blockers on the corrected QT (QTc), we conducted a randomized, controlled trial of opioid-addicted subjects. METHODS: We analyzed 12-lead electrocardiograms collected at baseline and every 4 weeks from 165 opioid-addicted participants in a 17-week randomized double-blind clinical trial of equally effective doses of levomethadyl, methadone, and buprenorphine at a major referral center. Analyses were limited to the 154 patients with a normal baseline QTc = (QT/ radical R-R) who had at least 1 subsequent in-treatment electrocardiogram. Patients were randomized to receive treatment with levomethadyl, methadone, or buprenorphine (hereinafter, levomethadyl, methadone, and buprenorphine groups, respectively). The prespecified end points were a QTc greater than 470 milliseconds in men (or >490 milliseconds in women), or an increase from baseline in QTc greater than 60 milliseconds. RESULTS: Baseline QTc was similar in the 3 groups. The levomethadyl and methadone groups were significantly more likely to manifest a QTc greater than 470 or 490 milliseconds (28% for the levomethadyl group vs 23% for the methadone group vs 0% for the buprenorphine group; P < .001) or an increase from baseline in QTc greater than 60 milliseconds (21% of the levomethadyl group [odds ratio, 15.8; 95% confidence interval, 3.7-67.1] and 12% of the methadone group [odds ratio, 8.4; 95% confidence interval, 1.9-36.4]) compared with the buprenorphine group (2% of subjects; P < .001). In subjects whose dosage of levomethadyl or methadone remained fixed over at least 8 weeks, the QTc continued to increase progressively over time (P = .08 for the levomethadyl group, P = .01 for the methadone group). CONCLUSION: Buprenorphine is associated with less QTc prolongation than levomethadyl or methadone and may be a safe alternative.

Levo-alpha-acetylmethadol (LAAM) versus methadone maintenance: 1-year treatment retention, outcomes and status.

AIMS: To compare levo-alpha-acetylmethadol (LAAM) and methadone maintenance (MM) on treatment retention, drug use during treatment and at follow-up, and abstinence. DESIGN: A two-group experimental design with patients assigned randomly (2:1) to receive fully subsidized LAAM or MM for 52 weeks. SETTING: A community clinic providing maintenance treatment in Los Angeles, California. PARTICIPANTS: A total of 315 treatment-seeking patients willing to be assigned randomly to treatment condition; 289 (91.7%) were interviewed at 52 weeks. INTERVENTION: LAAM or MM, plus ancillary services available to all patients. Medication dose varied according to clinical judgement. MEASUREMENTS: Treatment retention and status at 52-week follow-up, weekly clinical urinalysis, self-reported drug use and research urinalysis on samples collected at follow-up. FINDINGS: LAAM participants were more likely to complete the planned 52 weeks (57.4%) than MM participants (46.2%) and were less likely to be discharged for arrest/incarceration. LAAM produced fewer during treatment clinic opiate-positive samples (M = 48.8) than MM (M = 62.3). Further, 24.4% on LAAM compared to 11.8% on MM were able to sustain at least 12 weeks of abstinence during the last 24 weeks of treatment. Opiate use at follow-up was lowest (50.9%) among LAAM participants in maintenance treatment. No adverse events, cardiological or otherwise, were observed with LAAM administration. CONCLUSIONS: LAAM is an effective medication for the treatment of opiate dependence in community clinics with numerous behavioral and clinical advantages. LAAM is more effective than MM in promoting retention and extended reduction in and abstinence from opiate use while in treatment.

Drug interactions between opioids and antiretroviral medications: interaction between methadone, LAAM, and delavirdine.

Understanding the drug interactions between antiretrovirals and opioid therapies may decrease toxicities and enhance adherence with improved HIV outcomes in opioid-dependent individuals. The authors report the results of a clinical pharmacology study designed to determine whether significant pharmacokinetic and/or pharmacodynamic interactions occur between the non-nucleoside reverse transcriptase inhibitor, delavirdine (DLV), and either methadone or levo-alpha acetyl methadol (LAAM) (n = 40). DLV significantly decreased methadone clearance (p = .018) and increased the methadone elimination half-life (p < .001) with a resultant increase in AUC of 19% and C(min)of 29%. The combined effect of DLV on the total concentration of LAAM and its active metabolites, norLAAM and dinorLAAM, was to significantly increase AUC by 43% (p < .001), C(max) by 30% (p = .013), and C(min) by 59% (p = .004) while decreasing T(max) (p = .05). Cognitive deficits over the seven-day study period as measured by the Mini-Mental State Examination, opioid withdrawal symptoms as measured by the Objective Opioid Withdrawal Scale, or complaints of adverse symptoms were not observed. Methadone and LAAM did not affect DLV concentrations. The findings from this study show that DLV treatment in methadone- or LAAM-maintained individuals results in altered opioid pharmacokinetics with an increased exposure and potential risk for opioid toxicity with methadone or LAAM treatment and an increased risk of cardiac toxicity with concomitant LAAM and DLV administration.

Blood-brain equilibration kinetics of levo-alpha-acetyl-methadol using a chronically instrumented sheep preparation.

1.--The delayed onset and long duration of action of the opioid agonist levo-alpha-acetyl-methadol (LAAM) has been attributed to the formation of active metabolites. However, at present, little is known about the time course of blood-brain equilibration of LAAM itself. 2.--The cerebral kinetics of LAAM were quantified using physiologically based kinetic models and a conscious chronically instrumented sheep preparation. Seven sheep were administered 4 min intravenous infusions of 30 mg LAAM. Concentrations of LAAM and N-demethylated metabolites (nor-LAAM and di-nor-LAAM) in whole blood (0-75 min) were measured using a validated HPLC assay. 3.--LAAM did not alter cerebral blood flow, mean arterial pressure or cause significant respiratory depression. Cardiac output was similar to baseline at 4 min, but decreased by 30% at 10 min and remained at this level for the duration of the 75 min study period. 4.--Cerebral kinetics were best described by a membrane-limited model, with a relatively slow blood-brain tissue equilibration half-life of 22 min due to intermediate permeability (56 ml min(-1)) and a large cerebral distribution volume (724 ml). 5.--In conclusion, pharmacokinetic-pharmacodynamic modelling of LAAM should account for the large equilibration delay between brain and blood caused by slow equilibration kinetics. This may account for some of the delay in onset of effect previously attributed to the delayed appearance of active metabolites in blood.

Levo-alpha-acetylmethadol (LAAM) versus methadone: treatment retention and opiate use.

AIMS: To compare the effects of levo-alpha-acetylmethadol (LAAM) and methadone maintenance (MM) on treatment retention and abstinence from opiate use. DESIGN: A two-group experimental design with patients randomly assigned (2 : 1 LAAM : MM) to receive LAAM (three doses per week) or methadone (daily dosing). SETTING: A community clinic in Los Angeles, California. PARTICIPANTS: A total of 315 patients seeking LAAM or methadone maintenance. INTERVENTION: LAAM or methadone maintenance, plus ancillary services available to all patients. LAAM and methadone dose levels varied according to clinical judgement. Electrocardiograms were administered to LAAM patients monthly. MEASUREMENTS: Treatment status at 26-week follow-up and number of days retained in treatment, weekly clinical urine tests and 26-week research urine test. FINDINGS: LAAM and methadone patients did not differ on treatment retention. LAAM patients were less likely to test positive for opiate use during treatment (40% versus 60%) and at 26-week follow up (39.8% versus 60.2%). Benefits of LAAM were confined to patients (n = 204) still in treatment at 26 weeks (33% positive in patients receiving LAAM and 61% in patients receiving methadone). No adverse events, cardiological or otherwise, were observed with LAAM administration. CONCLUSIONS: LAAM is an effective medication for the treatment of opiate dependence with clinical advantages due not only to the reduction of opiate use but also to the alternate-day dosing schedule. LAAM may be more effective than methadone in promoting abstinence from opiate use among patients for whom LAAM is an acceptable alternative to methadone.

A placebo controlled, double-blind study of mecamylamine treatment for cocaine dependence in patients enrolled in an opiate replacement program.

A placebo controlled, double-blind trial of mecamylamine treatment of cocaine dependence was performed in methadone or LAAM maintained subjects who met DSM-IV criteria for cocaine dependence. After an eight-week placebo run-in screening period, 35 subjects were randomly assigned to receive either mecamylamine (6 mg/day) or placebo transdermal patches for a 16-week treatment period. Outcome measures included quantitative urine benzoylecognine (BE) levels, self-report of cocaine use, cocaine craving, global impression scores, mood, retention, and safety. Mecamylamine was well tolerated, and study retention did not differ by treatment group. Evidence for cocaine use, based on urine BE levels and cocaine abstinence rates, did not differ by treatment group. Self reported cocaine use, cocaine craving, and global impression scores showed moderate improvement in both groups, with a significantly greater reduction in cocaine craving (p < 0.05) and self-rated severity of cocaine dependence (p < 0.05) in the placebo group. This pilot study does not support the effectiveness of mecamylamine for the treatment of cocaine dependence in methadone or LAAM maintained patients.

Ketoconazole, a cytochrome P450 3A4 inhibitor, markedly increases concentrations of levo-acetyl-alpha-methadol in opioid-naive individuals.

BACKGROUND: Levo-acetyl-alpha-methadol (LAAM) exerts most of it mu-agonist activity through the action of its 2 N-demethylation metabolites, norLAAM and dinorLAAM. The N-demethylation of LAAM to norLAAM and norLAAM to dinorLAAM is primarily performed by cytochrome P450s (CYP) in the 3A family. No previous studies have been conducted to determine the effect of in vivo inhibition of CYP3A on the pharmacokinetics and pharmacodynamics of LAAM. METHODS: Oral LAAM (5 mg/70 kg) was administered on 2 occasions in a single-blind, randomized crossover design to 13 opioid-naive subjects (6 women and 7 men) 1 hour after pretreatment with 400 mg ketoconazole or placebo. Blood and urine samples were collected at defined intervals over 240- and 96-hour periods, respectively; LAAM, norLAAM, and dinorLAAM concentrations were determined by liquid chromatography-tandem mass spectrometry. Physiologic and subjective measures were collected for up to 72 hours. RESULTS: Results are presented as the geometric mean with 90% confidence intervals of individual ratios of ketoconazole to placebo sessions. Coadministration of ketoconazole and LAAM resulted in a 3.22-fold (2.53-4.10, P <.001) and 5.29-fold (4.24-6.61, P <.001) increase in the maximum plasma concentration (Cmax) and area under the curve (AUC) of LAAM. The values for time to Cmax (tmax) of norLAAM and dinorLAAM were increased 2.43-fold (1.92-3.08, P <.001) and 11.6-fold (8.36-16.1, P <.001), with 0.77-fold (0.67-0.87, P <.005) and 0.55-fold (0.49-0.60, P <.001) decreases in their respective Cmax values. The AUCs of norLAAM and dinorLAAM were increased 2.25-fold (1.96-2.58, P <.001) and 1.21-fold (1.12-1.32, P <.005), respectively. Pupil diameter was significantly decreased by LAAM after both placebo and ketoconazole pretreatment; ketoconazole increased the tmax for miosis 2.92-fold (2.01-4.25, P <.001). Other physiologic measures and numerous subjective effects measures were significantly affected by LAAM; however, few significant effects of ketoconazole pretreatment were observed on these outcomes. CONCLUSION: A single dose of ketoconazole causes a significant pharmacokinetic drug interaction with a single dose of LAAM that results in increased LAAM concentrations relative to norLAAM and dinorLAAM at early time points. Coadministration also results in prolongation of the appearance of its active metabolites and a concomitant prolongation of miosis, a sensitive dynamic index of mu-opioid action. The clinically relevant increase in LAAM concentrations and prolongation of plasma LAAM metabolites may affect physiologic function, such as QT intervals, suggesting that coadministration of LAAM and CYP3A4 inhibitors should be contraindicated.

Treatment needs associated with pain in substance use disorder patients: implications for concurrent treatment.

Although pain problems are prevalent in substance use disorder (SUD) patients, the special treatment needs of SUD patients with pain have not been investigated. This study examines the problems and behaviors associated with reported pain among veterans treated at eight opioid substitution treatment clinics. Patients reporting pain had more severe medical and psychiatric problems and greater health care utilization. Pain was associated with an increased propensity for misuse of substances with analgesic effects, suggesting that ongoing pain contributes to an altered and more severe pattern of drug-seeking behavior. Patients without pain rarely abused sedatives or opioid medication, indicating that misuse of these substances is unique to co-morbid pain and SUD patients. Patients reporting pain did not differ from patients without pain in use of heroin, alcohol, cocaine or in injection practices, demonstrating that they are truly SUD patients in need of SUD treatment. Pain complicates the treatment of SUD and should be addressed as an important co-morbidity during treatment.

Feasibility of referring drug users from a needle exchange program into an addiction treatment program: experience with a mobile treatment van and LAAM maintenance.

We evaluated program entry, retention, and early treatment response of needle exchange program (NEP) attenders referred to a drug treatment program using levomethadyl acetate hydrochloride (LAAM). Of 163 referrals, 114 (70%) entered the program, and 84% were retained for at least 90 days. Comparing baseline and follow-up visits after 1 month, there were significant reductions in the Addiction Severity Index subscale scores for drug and alcohol use and legal situation. We observed a 31% and 22% reduction in heroin- and cocaine-positive urine tests, respectively (p < .0001). Although LAAM is no longer considered a first line treatment for heroin addiction, these results demonstrate the feasibility of utilizing long-acting agonist therapies such as LAAM to treat opioid dependence among NEP attenders.

The use of levo-alpha-acetylmethadol (LAAM) in methadone patients who have not achieved heroin abstinence.

Levo-alpha-acetylmethadol (LAAM) pharmacotherapy was offered to twelve patients who continued illicit opioid abuse after > or = eleven months in methadone maintenance treatment. After 6-8 weeks on LAAM, plasma concentrations of the norLAAM metabolite varied significantly by LAAM dosing day, plasma adrenocorticotropin (ACTH) concentrations were significantly increased compared to methadone, and two of the seven subjects remaining in LAAM treatment were free of illicit opioids and nonprescribed methadone. After one year, one of five remaining subjects was using illicit opioids, and three were using non-prescribed methadone. While subject acceptance of LAAM was high, subjects were not in a "steady-state," with evidence of ongoing illicit opioid abuse.

Dialectical behavior therapy versus comprehensive validation therapy plus 12-step for the treatment of opioid dependent women meeting criteria for borderline personality disorder.

We conducted a randomized controlled trial to evaluate whether dialectical behavior therapy (DBT), a treatment that synthesizes behavioral change with radical acceptance strategies, would be more effective for heroin-dependent women with borderline personality disorder (N = 23) than Comprehensive Validation Therapy with 12-Step (CVT + 12S), a manualized approach that provided the major acceptance-based strategies used in DBT in combination with participation in 12-Step programs. In addition to psychosocial treatment, subjects also received concurrent opiate agonist therapy with adequate doses of LAAM (thrice weekly; modal dose 90/90/130 mg). Treatment lasted for 12 months. Drug use outcomes were measured via thrice-weekly urinalyses and self-report. Three major findings emerged. First, results of urinalyses indicated that both treatment conditions were effective in reducing opiate use relative to baseline. At 16 months post-randomization (4 months post-treatment), all participants had a low proportion of opiate-positive urinalyses (27% in DBT; 33% in CVT + 12S). With regard to between-condition differences, participants assigned to DBT maintained reductions in mean opiate use through 12 months of active treatment while those assigned to CVT + 12S significantly increased opiate use during the last 4 months of treatment. Second, CVT + 12S retained all 12 participants for the entire year of treatment, compared to a 64% retention rate in DBT. Third, at both post-treatment and at the 16-month follow-up assessment, subjects in both treatment conditions showed significant overall reductions in level of psychopathology relative to baseline. A noteworthy secondary finding was that DBT participants were significantly more accurate in their self-report of opiate use than were those assigned to CVT + 12S.