Search

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). Withinparticipant 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. Refereed/Peer-reviewed

Although the long-acting opiate methadone is commonly used to treat drug addiction, relatively little is known about the effects of withdrawal from this drug in preclinical models. The current study examined affective, neuroendocrine, and somatic signs of withdrawal from the longer-acting methadone derivative l-alpha-acetylmethydol (LAAM) in rats. Anxiety-like behavior during both spontaneous and antagonist-precipitated withdrawal was measured by potentiation of the startle reflex. Withdrawal elevated corticosterone and somatic signs and blunted circadian variations in baseline startle responding. In addition, fear to an explicit, Pavlovian conditioned stimulus (fear-potentiated startle) was enhanced. These data suggest that anxiety-like behavior as measured using potentiated startle responding does not emerge spontaneously during withdrawal from chronic opiate exposure – in contrast to withdrawal from acute drug exposure – but rather is manifested as exaggerated fear in response to explicit threat cues.

Introduction: Levo-Alpha-Acetylmethadol (LAAM) is a synthetic opioid analgesic with μ-agonistic activity and a long duration of action. There are several, almost exclusively US American studies showing the efficacy of LAAM as a maintenance drug which has the advantage that it needs to be administered only three times a week. LAAM is currently not marketed in EU countries due to cardiac complications. We report on the first European multi-center, parallel group, flexible dose, open-label, randomized clinical trial comparing LAAM and methadone in patients with opioid dependence. Methods: Eighty-four opioid addicts in ongoing maintenance treatment with stable methadone doses were treated with methadone under study conditions for 5 weeks (run-in phase), then randomly assigned to a methadone (n=41) or a LAAM (n=43) group. Study duration was 24 weeks after randomization. Objective measures (drug urine screenings, retention rate), subjective measures (symptoms of withdrawal and craving, report of substance use), and safety data were collected weekly. The main outcome criterion was the number of opiate-free urine samples per number of weeks of study participation. Results: Non-inferiority was shown for LAAM compared to methadone. Both substances were well tolerated. There were no clinical cardiac complications in either group. Discussion: Our study confirmed the results of previous investigations with LAAM as being efficacious and well tolerated in opioid dependence. A discussion to reconsider the availability of LAAM is recommended.

This study empirically tested one component of a comprehensive model of the role of religiosity and spirituality (R/S) in drug treatment that is presented as a companion article in this special issue. Data collected from individuals dependent on heroin receiving narcotic replacement therapy were used to assess the effects of R/S on drug treatment outcomes. Based on their R and S scores, participants were assigned to one of four groups: those whose scores remained consistently high across the 12-month study period were compared to those whose scores were consistently low, increased, or decreased across the same period. Results indicated that at both study completion (12 months after admission) and 6 months after that participants in the consistently high and increasing spirituality groups self-reported significantly fewer days of heroin and cocaine/crack use than those in the consistently low group (p < 0.05). There were no significant differences among the religiosity groups on self-reported heroin or cocaine/crack use. Results from chi(2) analyses indicated that at 12 months the results of urinalysis for the presence of opiates, but not cocaine/crack, were dependent on spirituality group membership (p < 0.01) but not religiosity group membership. Results also indicated that at the 6-month follow-up, there were significantly more participants in the decreasing group who were not in maintenance treatment who had a positive urinalysis and fewer in the increasing group than would be expected if the two variables were independent (p < 0.05). Implications for addictions health services are discussed.

Methadone and L-α-acetylmethadol (LAAM) are used as treatment for opiate addiction. Using a cellular model, we aimed to determine if methadone, LAAM and their main metabolites are substrates of the human P-glycoprotein transporter (P-gp), which is encoded by the ABCB1 gene, and whether methadone transport exhibits stereoselectivity. Pig kidney epithelial cells (control) and human ABCB1-transfected cells were incubated with methadone, LAAM and their metabolites, and their intra- and extracellular concentrations were measured. The intra- to extracellular ratios of methadone, LAAM and their metabolites were all decreased in ABCB1-transfected cells compared to controls (p < 0.05), thus indicating that they are substrates of P-gp. A weak stereoselectivity in methadone transport was observed towards the (S)-enantiomer. P-gp may therefore affect the pharmacokinetics and pharmacodynamics of methadone and LAAM.

Retention in Opioid Agonist Therapy (OAT) is associated with reductions in substance use, HIV risk behavior, and criminal activities in opioid dependent patients. To improve the effectiveness of treatment for opioid dependence, it is important to identify predisposing characteristics and provider-related variables that predict retention in OAT. Participants include 258 veterans enrolled in 8 outpatient methadone/l-alpha-acetylmethadol (LAAM) treatment programs. Signal detection analysis was utilized to identify variables predictive of 1-year retention and to identify the optimal cut-offs for significant predictors. Provider-related variables play a vital role in predicting retention in OAT programs, as higher methadone dose (> or =59 mg/day) and greater treatment satisfaction were among the strongest predictors of retention at 1-year follow-up.

We evaluated a case management intervention to increase treatment entry among injecting drug users referred from a needle exchange program (NEP). A randomized trial of a strengths based case management (intervention) versus passive referral (control) was conducted among NEP attenders requesting and receiving referrals to subsidized, publicly funded opiate agonist treatment programs in Baltimore, MD. Logistic regression identified predictors of treatment entry within 7 days, confirmed through treatment program records. Of 247 potential subjects, 245 (99%) participated. HIV prevalence was 19%. Overall, 34% entered treatment within 7 days (intervention: 40% versus control: 26%, p = 0.03). In a multivariate “intention to treat’ model (i.e., ignoring the amount of case management actually received), those randomized to case management were more likely to enter treatment within 7 days. Additional ‘as treated’ analyses revealed that participants who received 30 min or more of case management within 7 days were 33% more likely to enter treatment and the active ingredient of case management activities was provision of transportation. These findings demonstrate the combined value of offering dedicated treatment referrals from NEP, case management and transportation in facilitating entry into drug abuse treatment. Such initiatives could be implemented at more than 140 needle exchange programs currently operating in the United States. These data also support the need for more accessible programs such as mobile or office-based drug abuse treatment.

In 1963, Professor Vincent P. Dole at the Rockefeller University formed a small team to develop a pharmacotherapy for the management of heroin addiction. They hypothesized that heroin addiction is a disease of the brain with behavioral manifestations, and not merely a personality disorder or criminal behavior and began to address the specific question of whether a long-acting opioid agonist could be used in the long-term maintenance treatment of heroin addiction. Over the next 35 years, many studies documented the safety, efficacy and effectiveness of methadone pharmacotherapy for heroin addiction, but Federal regulations and stigmatization of heroin addiction prevented implementation of treatment. Finally, in 1999, NIH published a report unequivocally supporting methadone maintenance pharmacotherapy for heroin addiction. Two other effective opioid agonist treatments have been developed: the even longer acting opioid agonist l-alpha-acetylmethadol (LAAM) has been approved for pharmacotherapy for heroin addiction, and still under study is the opioid partial agonist-antagonist buprenorphine-naloxone combination. A variety of studies, both laboratory based and clinical, have revealed the mechanisms of action of long-acting opioid agonists in treatment, including prevention of disruption of molecular, cellular and physiologic events and, in fact, allowing normalization of those functions disrupted by chronic heroin use. Recent molecular biological studies have revealed single nucleotide polymorphisms of the human mu opioid receptor gene; the mu opioid receptor is the site of action of heroin, the major opiate drug of abuse, analgesic agents such as morphine, and the major treatment agents for heroin addiction. These findings support the early hypotheses of our laboratory that addiction may be due to a combination of genetic, drug-induced and environmental (including behavioral) factors and also, that atypical stress responsivity may contribute to the acquisition and persistence of, as well as relapse to, use of addictive drugs.

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.

This study examined (1) predictors of treatment outcome for opioid-dependent participants in a single-site controlled trial comparing methadone, buprenorphine, and LAAM treatments and (2) the extent to which various subpopulations of patients may have more successful outcomes with each medication. The relationships between patient demographics, drug use history, and psychological status and outcome measures of treatment retention, opiate use, and cocaine use were assessed. We believe this study to be the first to demonstrate that predictors of treatment success appear to be largely similar in LAAM, buprenorphine, and methadone treatment for opioid dependence. We did not find any factors that would strongly guide selection of one medication over others.

Because prisoners with preincarceration heroin dependence typically relapse following release, a pilot study examined a novel opioid agonist maintenance program whereby consenting males initiated levo-alpha-acetylmethadol (LAAM) treatment shortly before release from prison with opportunity to continue maintenance in the community. Treated prisoners (experimental group) were compared with controls who received community treatment referral information only and prisoners who withdrew from treatment prior to medication regarding treatment participation and community adjustment during nine months post-release. Nineteen of 20 (95%) prisoners who initiated maintenance in prison entered community treatment, compared with 3 of 31 (10%) controls, and 1 of 13 (8%) who withdrew. Moreover, 53% of experimental participants remained in community treatment at least six months, while no other participants did so. Differences in heroin use and criminal involvement between experimental participants and each of the other two groups, while not consistently statistically significant, uniformly favored the experimental group. Despite study limitations, robust findings regarding treatment attendance suggest that this intervention is highly promising.

Aims The study estimated serious adverse event (SAE) rates among entrants to pharmacotherapies for opioid dependence, during treatment and after leaving treatment. Design A longitudinal study based on data from 12 trials included in the Australian National Evaluation of Pharmacotherapies for Opioid Dependence (NEPOD). Participants and settings A total of 1.244 heroin users and methadone patients treated in hospital, community and GP settings. Intervention Six trials included detoxification; all included treatment with methadone, buprenorphine, levo-alpha-acetyl-methadol (LAAM) or naltrexone. Findings During 394 person-years of observation, 79 SAEs of 28 types were recorded. Naltrexone participants experienced 39 overdoses per 100 person-years after leaving treatment (44% occurred within 2 weeks after stopping naltrexone). This was eight times the rate recorded among participants who left agonist treatment. Rates of all other SAEs were similar during treatment versus out of treatment, for both naltrexone-treated and agonist-treated participants. Five deaths occurred, all among participants who had left treatment, at a rate of six per 100 person-years. Total SAE rates during naltrexone and agonist treatments were similar (20, 14 per 100 person-years, respectively). Total SAE and death rates observed among participants who had left treatment were three and 19 times the corresponding rates during treatment. Conclusions Individuals who leave pharmacotherapies for opioid dependence experience higher overdose and death rates compared with those in treatment. This may be due partly to a participant self-selection effect rather than entirely to pharmacotherapy being protective. Clinicians should alert naltrexone treatment patients in particular about heroin overdose risks. Duty of care may extend beyond cessation of dosing.

Understanding drug interactions between antiretrovirals and opiate therapies may decrease toxicities and enhance adherence, with improved HIV outcomes in injection drug users. We report results of a clinical pharmacology study designed to examine the interaction of the protease inhibitor, nelfinavir, with methadone and LAAM (N = 48). Nelfinavir decreased methadone exposure, but no withdrawal was observed over the five day study period. LAAM and dinorLAAM concentrations were decreased, while norLAAM concentrations were increased, with minimal overall change in LAAM/metabolite exposure. Methadone and LAAM did not affect nelfinavir concentrations, but methadone decreased M8 metabolite exposure. While no toxicities were observed, clinicians should be aware of the potential for drug interactions when patients require treatment with nelfinavir and these opiate medications.

Opiate addiction is a chronic, relapsing disorder. Left untreated, high morbidity and mortality rates are seen. Pharmacotherapies for this disorder using mu opiate agonists (methadone and levomethadyl acetate) and partial agonists have been developed in the last 40 years. Agonist pharmacotherapy with oral methadone for the treatment of opiate dependence was developed in clinical pharmacology studies at Rockefeller University by Dole, Nyswander, and Kreek. Further studies by this laboratory and others established that moderate to high dose treatment with methadone (80-120 mg) reduced or eliminated opiate use in outpatient settings with consequent reductions in morbidity and up to 4-fold reductions in mortality. Levomethadyl acetate (LAAM), a congener of methadone, is biotransformed to active metabolites responsible for its longer duration of action. The Federal Regulations regarding the dispensation of methadone and LAAM have recently been revised to facilitate the treatment of patients under a "medical maintenance" model. Future regulatory reform will likely involve the establishment of rules for "office based opioid treatment."

Effective postincarceration treatment for individuals with preincarceration heroin dependence is urgently needed because relapse typically follows release. This article presents first-year findings from a unique 2-year pilot study of opioid agonist maintenance treatment initiated in prison and continued in the community. Incarcerated males with preincarceration heroin dependence were randomly assigned to Levo-alpha-acetylmethadol (LAAM) maintenance or control conditions 3 months before release. Approximately 92% of eligible inmates volunteered to participate; 36 of 58 subjects who were eligible and randomly assigned to LAAM maintenance successfully initiated treatment. Twenty-eight of these continued on LAAM until release; 22 (78.6%) entered community-based maintenance treatment; and 11 (50%) remained in treatment at least 6 months postrelease. Changes in LAAM's labeling because of its association with cardiac arrhythmias now makes it a second-line treatment for heroin dependence, unsuitable for treatment initiation. Nonetheless, study findings may also be applicable to methadone maintenance treatment, suggesting such treatment may be a promising means of engaging prisoners with preincarceration heroin dependence into continuing treatment.

The efficacy of methadone maintenance in opioid addiction was assessed in terms of programme retention rate and reduction of illicit opioid use by means of a meta-analysis of randomised, controlled and double blind clinical trials. The results were compared with interventions using buprenorphine and levo-acetylmethadol (LAAM). Trials were identified from the PubMed database from 1966 to December 1999 using the major medical subject headings 'methadone' and 'randomised controlled trial'. Data for a total of 1944 opioid-dependent patients from 13 studies were analysed. Sixty-four percent of patients received methadone, administered either as fixed or adjusted doses. Thus, 890 patients receivedor = 50 mg/day (high dose group) and 392 were given50 mg/day (low dose group). Of 662 controls, 131 received placebo, 350 buprenorphine (265 at dosesor = 8 mg/day and 85 at doses8 mg/day) and 181 LAAM. High doses of methadone were more effective than low doses in the reduction of illicit opioid use (odds ratio [OR] 1.72, 95% confidence interval [CI] 1.26--2.36). High doses of methadone were significantly more effective than low doses of buprenorphine (8 mg/day) for retention rates and illicit opioid use, but similar to high doses of buprenorphine (or = 8 mg/day) for both parameters. Patients treated with LAAM had more risk of failure of retention than those receiving high doses of methadone (OR 1.92, 95% CI 1.32--2.78). It is proposed that in agonist-maintenance programmes, oral methadone at doses of 50 mg/day or higher is the drug of choice for opioid dependence.

Background The scientific literature examining effective treatments for opioid-dependent adults clearly indicates that pharmacotherapy is a necessary and acceptable component. Nevertheless, no reviews have been published that systematically assess the effectiveness of pharmacological maintenance treatment in adolescents. Objectives To assess the effectiveness of any maintenance treatment alone or in combination with psychosocial intervention compared to no intervention, other pharmacological intervention or psychosocial interventions for retaining adolescents in treatment, reducing the use of substances and improving health and social status. Search methods We searched the Cochrane Drugs and Alcohol Group's Trials Register (January 2014), the Cochrane Central Register of Controlled Trials (2014, Issue 1), PubMed (January 1966 to January 2014), EMBASE (January 1980 to January 2014), CINAHL (January 1982 to January 2014), Web of Science (1991 to January 2014) and reference lists of articles. Selection criteria Randomised and controlled clinical trials of any maintenance pharmacological interventions either alone or associated with psychosocial intervention compared with no intervention, placebo, other pharmacological intervention, pharmacological detoxification or psychosocial intervention in adolescents (13 to 18 years). Data collection and analysis We used the standard methodological procedures expected by The Cochrane Collaboration. Main results We included two trials involving 189 participants. One study, with 35 participants, compared methadone with levo-alpha-acetylmethadol (LAAM) for maintenance treatment lasting 16 weeks, after which patients were detoxified. The other study, with 154 participants, compared maintenance treatment with buprenorphine-naloxone and detoxification with buprenorphine. We did not perform meta-analysis because the two studies assessed different comparisons. In the study comparing methadone and LAAM, the authors declared that there was no difference in the use of a substance of abuse or social functioning (data not shown). The quality of the evidence was very low. No side effects, such as nausea, vomiting, constipation, weakness or fatigue, were reported by study participants. In the comparison between buprenorphine maintenance and buprenorphine detoxification, maintenance treatment appeared to be more efficacious in retaining patients in treatment (drop-out risk ratio (RR) 0.37; 95% confidence interval (CI) 0.26 to 0.54), but not in reducing the number of patients with a positive urine test at the end of the study (RR 0.97; 95% CI 0.78 to 1.22). Self reported opioid use at one-year follow-up was significantly lower in the maintenance group, even though both groups reported a high level of opioid use (RR 0.73; 95% CI 0.57 to 0.95). More patients in the maintenance group were enrolled in other addiction treatment programmes at 12-month follow-up (RR 1.33; 95% CI 0.94 to 1.88). The quality of the evidence was low. No serious side effects attributable to buprenorphine-naloxone were reported by study participants and no patients were removed from the study due to side effects. The most common side effect was headache, which was reported by 16% to 21% of patients in both groups Authors' conclusions It is difficult to draft conclusions on the basis of only two trials. One of the possible reasons for the lack of evidence could be the difficulty of conducting trials with young people for practical and ethical reasons. There is an urgent need for further randomised controlled trials comparing maintenance treatment with detoxification treatment or psychosocial treatment alone before carrying out studies that compare different pharmacological maintenance treatments. These studies should have long follow-up and measure relapse rates after the end of treatment and social functioning (integration at school or at work, family relationships).

A patient undergoing management of heroin dependency with high dosages of the long-acting methadone derivative, levomethadyl acetate HCl (LAAM; ORLAAM) developed a prolonged QTc interval and polymorphic QRS complexes on EKG consistent with torsades de pointes (TdP). The patient was taking other drugs known to prolong the QTc interval (fluoxetine and IV cocaine), and those known to antagonize the activity of the P450 enzymes responsible for the metabolism of LAAM and its active metabolite (fluoxetine, cocaine and marijuana). No previous reports have appeared in the literature attributing this adverse event to LAAM therapy; however, five similar cases have been reported to the manufacturer. Animal studies indicate that LAAM and metabolites prolong the action potential duration of myocardial cells. We propose that predisposed patients on high doses of LAAM may be at risk for developing TdP. Patients being treated with LAAM should receive dosages consistent with guidelines and be evaluated for concomitant diseases, interacting drug therapies, and EKG abnormalities.

Levo-Alpha Acetyl Methadol, or LAAM, is a medication therapy for individuals addicted to opiates that provides an alternative to methadone. Because it is administered only three times a week and, therefore, requires fewer clinic trips, patient acceptance can be higher than with methadone. While blocking the effects of other opiates and preventing withdrawal, LAAM does not produce a subjective high. However, because most patients are not familiar with LAAM, they may be initially more anxious and need more counseling and support when receiving the medication than they would with the more familiar methadone medication. On balance, LAAM enables clinic administrators and counselors to offer an alternative medication to methadone that some clients prefer once they become adjusted to it because of LAAM's even, stable effect. Through hypothetical but true-to-life case studies of LAAM use, it is possible to gain a clearer understanding of the advantages and drawbacks of using LAAM.

This study examined outcomes and their predictors among 181 probationers enrolling in opioid agonist maintenance with methadone or levo-alpha-acetylmethadol (LAAM). Participants were interviewed at treatment entry and 2-, 6-, and 12-month follow-ups. Treatment retention and frequency of heroin use, cocaine use, and income-generating criminal activity were examined using survival and longitudinal analyses. Participants reported marked reductions in drug use and crime relative to treatment entry. A number of patient characteristics associated with various outcomes were identified. The findings support engaging probationers in treatment and highlight patient factors that might influence outcomes.

Introduction Oral fluid testing is widely used for detecting drug exposure, but data describing methadone and metabolites in oral fluid during pharmacotherapy for opioid-dependence are relatively limited. Methods 414 oral fluid specimens from 16 opioid-dependent pregnant women receiving daily methadone were analyzed for methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), and methadol by liquid chromatography-mass spectrometry. Results All oral fluid specimens contained methadone greater than 1 ng/mL; 88% were positive for EDDP and 12% for methadol. Over 95% of oral fluid specimens exceeded the 20 ng/mL methadone cutoff set by the European Driving Under the Influence of Drugs, Alcohol and Medicines (DRUID) study. Methadone and EDDP oral fluid concentrations were highly variable within and between participants, did not predict methadone dose, but were negatively correlated with pH. Conclusion Methadone was readily identified in oral fluid at concentrations greater than 20 ng/mL following daily 30–110 mg/day methadone pharmacotherapy. As no specimens contained only EDDP or methadol, there was no advantage to including these analytes for identification of methadone exposure. As nearly all oral fluid specimens from methadone-maintained patients exceeded the DRUID guideline, the 20 ng/mL cutoff appears to be sensitive enough to detect daily methadone exposure; however, additional indicators of behavioral and/or motor impairment would be necessary to provide evidence of driving impairment.

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 hERGassociated channel blockers on the corrected QT (QTc), we conducted a randomized, controlled trial of opioidaddicted subjects. Methods: We analyzed 12-lead electrocardiograms collected at baseline and every 4 weeks from 165 opioidaddicted participants in a 17-week randomized doubleblind 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/ 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 (or490 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.

Pooled self-report and physiological data from 32 male and 15 female methadone or levo-α-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 minutes post-injection. Males and females were each divided by the median split methadone 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 subscales of the Adjective Rating Scale, and the Lysergic acid diethyl amine (LSD) sub-scale of the Addiction Research Center Inventory at 20 minutes 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.

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.

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.

GERAK, L. R., R. GALICI AND C. P. FRANCE. Self administration of cocaine in monkeys receiving LAAM acutely or chronically. PHYSIOL BEHAV 00(0) 000-000, 2007. Polydrug abuse remains a common problem among opioid abusers as well as patients in opioid maintenance programs. Although cocaine abuse has been reported in patients receiving methadone, the incidence of cocaine use in patients receiving l -alpha-acetylmethadol (LAAM) has not been well established. The goal of this study was to determine whether acute or chronic administration of LAAM modified the reinforcing effects of cocaine using a self-administration procedure in rhesus monkeys. Four monkeys responded under a fixed ratio (FR) 30 schedule to receive i.v. infusions of cocaine (0.0032–0.32 mg/kg/infusion) in the absence of other treatment, after acute LAAM administration (0.1–1.0 mg/kg, s.c.), and during daily administration of 1.0 mg/kg of LAAM. Cocaine maintained self-administration responding that exceeded responding maintained by saline; acutely administered LAAM had small and variable effects on self administration of cocaine. Daily LAAM administration increased the number of infusions received of at least one dose of cocaine. These studies indicated that LAAM administration did not attenuate the reinforcing effects of cocaine, suggesting that LAAM would not likely alter cocaine abuse in patients undergoing treatment for opioid abuse.

The aim of this study was to determine how the treatment needs and outcomes of polysubstance-using patients entering opioid-substitution treatment (OST) may be affected if the patient had a parent with substance-use problems.This prospective observational study examined outcomes of 255 patients (97% male) entering OST at eight clinics in the Veterans Health Administration. Self-reported substance-use outcomes in the first year of treatment were compared between patients with (n = 121) and without (n = 134) a parent with substance-use problems. The association between receipt of practice guideline-recommended elements of care and treatment outcome was examined.Parent history-positive patients had greater drug use at 6 months, but by 12 months they had reduced their drug use to the same extent as parent history-negative patients. Ongoing methadone (Dolophine, Methadose) maintenance was associated with improved outcomes of drug use in parent history-negative patients; however, parent history-positive patients who ended methadone maintenance reduced drug use as much as those who continued treatment. The association between treatment received and outcome differed in these populations. In parent history-negative patients, reduced severity of substance use at 1 year was predicted solely by receiving methadone for a greater number of days. In parent history-positive patients, reduced severity of substance use was predicted by receiving methadone for fewer days, by greater satisfaction with and receipt of counseling services, and by lesser tendency for providers to encourage a reduction in methadone use.The importance of counseling and medication components of OST may differ depending on family history. For parent history-negative patients, medication maintenance may be more therapeutically necessary.

Injection drug use is a common risk factor for HIV infection, and opioid use and dependence is the underlying condition that often fuels HIV risk behaviour and subsequent HIV seroconversion among injection drug users (IDUs). Treatment of opioid dependence often requires continued opioid administration in the form of substitution therapy, which means that opioid-using IDUs often continue receiving opioids even after cessation of illicit drug use. The concurrent use of both antiretrovirals and opioids in HIV-positive individuals is thus common. This review was undertaken to summarise current knowledge on the interactions between the opioids and antiretrovirals and to make recommendations on the treatment of HIV-positive opioid-dependent patients.

Buprenorphine may be used to treat opioid dependence in office-based settings, but treatment models are needed to ensure access to psychosocial services needed by many patients. We describe a novel buprenorphine treatment program colocated with methadone maintenance and outpatient chemical dependency services. We conducted a retrospective chart review of the first 40 consecutive patients initiating buprenorphine treatment in this program to determine characteristics associated with treatment retention. Exclusion criteria were current alcohol or benzodiazepine dependence. Secondary drug users and patients who were psychiatrically or medically ill were included. At 6 months, 60% (n = 24) were retained, 13% (n = 5) tested positive for opiates, and 25% (n = 10) tested positive for secondary substances. Patients who were older (odds ratio [OR] per year of age = 1.1, confidence interval [CI] = 1.0-1.2) and those who were employed (OR = 9.8, CI = 1.8-53.1) were more likely to remain in treatment, but other variables were not associated with retention. Our experience demonstrates that buprenorphine can be successfully integrated into outpatient substance abuse treatment.

The efficacies of three opioid substitution medications for reducing HIV risk behaviors in opioid-dependent patients were assessed in a randomized double-blind clinical trial comparing levomethadyl acetate [corrected] (LAAM), buprenorphine (BUP), and methadone (METH). Individually optimized flexible dosing was used for each group, with weekly possible doses of 255-391 mg of LAAM, 56-112 mg of BUP, and 420-700 mg of METH. An interview regarding specific HIV risk behaviors, including injecting, equipment sharing, and sexual activity, yielded data for pretreatment and four in-study time points for 137 subjects. Declines in risk behaviors during treatment were evident in all groups for most measures of injecting and equipment sharing. Only the METH group showed consistent declines in measures of sexual behaviors. These results demonstrate that all three medications can be highly effective in decreasing HIV risk behaviors when the dose is optimized. Reductions in sexual behaviors for the METH group are consistent with known METH side effects.

AIMS: To determine the in vitro kinetics of morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) formation and the inhibition potential by methadone enantiomers and structurally related opioids. METHODS: M3G and M6G formation kinetics from morphine were determined using microsomes from five human livers. Inhibition of glucuronide formation was investigated with eight inhibitors (100 microm) and the mechanism of inhibition determined for (R)- and (S)-methadone (70-500 microm) using three microsomal samples. RESULTS: Glucuronide formation displayed single enzyme kinetics. The M3G Vmax (mean+/-SD) was 4.8-fold greater than M6G Vmax (555+/-110 vs. 115+/-19 nmol mg-1 protein h-1; P=0.006, mean of difference 439; 95% confidence interval 313, 565 nmol mg-1 protein h-1). Km values for M3G and M6G formation were not significantly different (1.12+/-0.37 vs. 1.11+/-0.31 mm; P=0.89, 0.02; -0.29, 0.32 mm). M3G and M6G formation was inhibited (P

To compare the effects of levo-alpha-acetylmethadol (LAAM) and methadone maintenance (MM) on treatment retention and abstinence from opiate use.A two-group experimental design with patients randomly assigned (2 : 1 LAAM : MM) to receive LAAM (three doses per week) or methadone (daily dosing).A community clinic in Los Angeles, California.A total of 315 patients seeking LAAM or methadone maintenance.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.Treatment status at 26-week follow-up and number of days retained in treatment, weekly clinical urine tests and 26-week research urine test.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.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.

Few clinical trials include sex as a factor. This analysis explored within-sex differences in response to opioid agonist medications. Males and females randomly assigned to buprenorphine, LAAM, or methadone were compared on opioid use and retention in treatment. Females receiving buprenorphine had less objective drug use than females receiving methadone, while males receiving LAAM had less objective drug use than males receiving buprenorphine. Retention in treatment was longer for both sexes receiving methadone versus LAAM. Within-subject change results indicate that all three medications benefit both sexes. Clinical trials should be designed to examine the impact of sex on outcomes.

Forty opioid substitution patients (methadone, n = 14; LAAM, n = 14; and buprenorphine, n = 12) who were participating in a study on the impact of opiate substitution treatment on driving ability and 22 non-opiate-using control subjects were administered 14.7 g/70 kg of alcohol in two separate sessions, one 2-3 hours before opioid pharmacotherapy dosing and the other 1-2 hours after dosing. The mean blood alcohol concentration (BAC) in the post-opioid dose session was significantly lower than that in the pre-opioid dose session (p.05). There was a significant effect of experimental group (LAAM, methadone, buprenorphine, or control) on BAC in sessions conducted 1-2 hours after the opioid substitution dose (p.01). There was a trend for a reduced effect of experimental group on BAC in the pre-opioid substitution dose session (p = .06). The BAC of non-opioid substitution control subjects was significantly higher than that of the LAAM (before and after LAAM dosing) and methadone (after methadone dosing; p.05) patients. These findings provide evidence for the first time of an interaction between opiates and alcohol in humans that is strongest at the time of peak opiate plasma levels in the hours after opioid dosing.

The aim of this study was to determine if substitution of daily methadone with second daily levo-alpha-acetylmethadol (LAAM) would convert non-holders on methadone into holders on LAAM, and to compare plasma concentration-time profiles of (R)-methadone with LAAM and its two metabolites. Sixteen stable methadone maintenance treatment participants (non-holders, n = 8) were randomly allocated to continue methadone for 3 months or switch to LAAM for 3 months, and then crossed over to the alternative drug for 3 months. At steady state, there were two testing sessions (24 h for methadone and 48 h for LAAM), during which opioid withdrawal severity, respiration rate and pupil diameter were measured 10-11 times and venous blood was collected 13-15 times. Ten age- and gender-matched controls underwent one 48-h test session. Areas under the withdrawal severity score versus time curve (AUC(0-47) hours for LAAM and controls; AUC(0-24) x 2 for methadone) were similar in holders on methadone and LAAM (P = 0.62), but were greater in non-holders when they were taking methadone than LAAM (P < 0.001). Respiratory depression and pupillary constriction were similar for LAAM and methadone. In comparison to (R)-methadone, plasma nor- and dinor-LAAM concentrations fluctuated little over the dosing interval. LAAM converted methadone non-holders into LAAM holders. LAAM may therefore be useful in selected MMT non-holders and improve retention in opioid treatment programs.

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.

While methadone is currently the primary pharmacotherapy used in the treatment of heroin dependence in Australia, levo-alpha-acetyl-methodol (LAAM) and buprenorphine are new pharmacotherapies that are being examined as alternatives to methadone maintenance treatment. The aim of this research is to consider the effects of the methadone, buprenorphine and LAAM, as used in maintenance pharmacotherapy for heroin dependence, upon simulated driving. Clients stabilised in methadone, LAAM and buprenorphine treatment programs for 3 months, and a control group of non-drug-using participants, took part in this study which involved operating a driving simulator over a 75 min period. All participants attended one session without alcohol and one session with alcohol at around the 0.05% blood alcohol level. Simulated driving skill was measured through standard deviations of lateral position, speed and steering wheel angle, and reaction time to a subsidiary task was also measured. While alcohol impaired all measures of driving performance, there were no differences in driving skills across the four participant groups. These findings suggest that typical community standards around driving safety should be applied to clients stabilised in methadone, LAAM and buprenorphine treatment. The findings are important in terms of the widespread implementation of these treatment options in Victoria given that a large proportion of pharmacotherapy clients drive.

The present study aimed to compare the efficacy of levo-alpha-acetylmethadol (LAAM) and methadone, as measured by retention in treatment and heroin use, in a randomized trial conducted under naturalistic conditions.This study is the first randomized trial comparing LAAM with methadone in the primary care setting. Participants were recruited through 29 medical practitioners working in specialist and generalist settings in Australia.Existing methadone maintenance patients, aged 18 years and over and able to give informed consent, were randomized to receive either LAAM or methadone. A total of 93 patients participated.After being trained in the use of LAAM, existing methadone prescribers were then able to determine an individually tailored treatment regimen for each patient. The trial was an open-label study. Methadone and LAAM dosing was supervised through local community pharmacies. Participation in ancillary services (e.g. counselling) was optional for all patients. The treatment period for the trial was 12 months.Baseline, 3-, 6- and 12-month interviews were conducted. Outcome measures were retention in treatment, self-reported heroin use and serious adverse events.There were no significant differences between LAAM and methadone on retention in treatment, nor heroin use. There was a trend for LAAM patients to have lower heroin use than methadone patients. Of the seven serious adverse events in the LAAM group, three were not drug-related. There were two dosing errors.This study demonstrates (a) the efficacy of LAAM as a treatment for heroin dependence, and (b) the capacity for LAAM to be effectively delivered in primary care settings by trained general practitioners and pharmacists. The next challenge is to resolve outstanding safety concerns with LAAM.

Given the difficulty of achieving sustained recovery, pharmacotherapy of opioid and cocaine addiction is more effective when combined with behavioral and psychosocial approaches. Effective pharmacotherapies for opioid dependence and withdrawal include methadone, L-alpha acetylmethadol (LAAM), naltrexone, buprenorphine, and clonidine. Treatment of cocaine addiction includes anti-craving agents, dopamine agonists or blocking agents, antidepressants, and treatment of co-morbid psychiatric disorders, but all with mixed results. In this paper, we discuss the use of medication in the context of general principles of opioid and cocaine addiction treatment. Both established medications and promising directions in pharmacotherapy will be addressed.

The agonists buprenorphine and l-alpha-acetylmethadol (LAAM) were introduced as alternatives to methadone for treatment of the adult opiate addict. The direct and indirect effects of these drugs on normal fetal growth and development are currently under investigation in our laboratory. The goal of this report is to provide part of the data necessary to assess the safety of LAAM in treatment of the pregnant opiate addict. To achieve this goal, the technique of dual perfusion of placental lobule was utilized to determine the kinetics for transplacental transfer of LAAM and its effects on the viability and functional parameters of the tissue. LAAM is rapidly metabolized to the pharmacologically active norLAAM that was also included in this investigation. The two opiates were transfused at their plasma levels in patients under treatment, a concentration of 35 ng/ml. The drugs exhibited similar pharmacokinetic profiles, characterized by an initial phase of distribution into placental tissue followed by their low transfer to the fetal circuit. During the 4-h experimental period, the transfused tissue retained significant amounts of LAAM and norLAAM, and neither drug was metabolized. LAAM did not affect placental tissue viability and functional parameters. However, norLAAM caused a significant decrease in the release of human chorionic gonadotropin. At this time, it is unclear whether a similar effect for norLAAM may occur in vivo and, if so, what the consequences would be on its role in implantation and normal fetal growth and development.