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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.

The trigger for liver regeneration, including shear stress, has been the subject of ongoing debate. Blood vessel-derived gaseous molecules carbon monoxide (CO) and nitric oxide (NO) regulate vascular tone and play an important role in liver regeneration. In heme oxygenase-1 (HO-1) transgenic mice, it has been shown that CO-mediated impairment of vasorelaxation is an NO-dependent event. We therefore studied liver regeneration in HO-1 overexpressing animals in dependency of NO availability. Mice were subjected to (2/3) hepatectomy and were treated with either cobalt protoporphyrin-IX for induction of CO-liberating HO-1, N(omega)-nitro-L-arginine methyl ester (L-NAME) for blockade of NO synthase (NOS) or both. Application of molsidomine in L-NAME treated animals served for resubstitution of NO. Vehicle-treated animals served as respective control animals. We examined 5-bromo-2'-deoxyuridine incorporation and proliferating cell nuclear antigen expression as well as HO-1 and NOS-2 protein levels. Intrahepatic red blood cell velocity and volumetric blood flow were evaluated by in vivo fluorescence microscopy as indicators for microvascular shear stress. Hepatic regeneration remained unaffected by L-NAME application for NOS blockade. However, NOS blockade in HO-1 induced animals caused increased 5-bromo-2'-deoxyuridine and proliferating cell nuclear antigen measures of liver regeneration. In parallel, these animals revealed increased velocities and volumetric blood flow in the terminal afferent vessels and postsinusoidal venules. These local hemodynamic changes including enhanced hepatocyte proliferation could be reversed by NO liberation via molsidomine. The present findings stress the role of NO to counterbalance vascular tone in HO-1 overexpressing animals for maintenance of adequate perfusion and salutary shear force within the hepatic microvasculature upon liver resection.

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.

Opioid- and cocaine-dependent participants ( N = 140) were randomly assigned to one of the following in a 12-week clinical trial: LAAM (30, 30, 39 mg/MWF) with contingency management (CM) procedures (LC); LAAM (30, 30, 39 mg/MWF) without CM (LY); LAAM (100, 100, 130 mg/MWF) with CM (HC); LAAM (100, 100, 130 mg/MWF) without CM (HY). Urine samples were collected thrice-weekly. In CM, each urine negative for both opioids and cocaine resulted in a voucher worth a certain monetary value that increased for consecutively drug-free urines. Subjects not assigned to CM received vouchers according to a yoked schedule. Vouchers were exchanged for mutually agreed upon goods and services. Groups generally did not differ on retention and baseline characteristics. Overall opioid use was least in the HC and HY groups; opioid use decreased most rapidly over time in the HC group relative to the HY, LC and LY groups. Overall cocaine use was least in the HC group relative to the HY, LC, and LY groups; cocaine use decreased over time most rapidly in the HC and LY groups. Abstinence from both was greatest in the HC group. Opioid withdrawal symptoms decreased most rapidly in the high-dose groups relative to the low-dose groups. These results suggest that an efficacious maintenance dose is necessary for contingencies to be effective in facilitating both opioid and cocaine abstinence.

In 1989, the National Institute on Drug Abuse (NIDA) established its Medications Development Program. This program has concentrated on developing pharmacotherapies for opiate and cocaine dependence and, more recently, for methamphetamine and cannabis dependence. The major goals of this program are to optimize existing treatments and to expand treatment options for physicians and patients. This review will concentrate on the development of pharmacotherapies for the following substance abuse disorders: opiate, cocaine, methamphetamine, and cannabis dependence. Left untreated, opiate and stimulant dependence are responsible for significant morbidity and mortality. For example, use of illicit opiates is associated with an increased risk of hepatitis C infection, HIV infection, and other medical consequences, e.g., an overdose. The NIDA Medications Development Program has had success in developing, with pharmaceutical partners, levomethadyl acetate, buprenorphine, and buprenorphine/naloxone for opiate dependence. Moreover, several marketed medications have shown promise in reducing cocaine use. Of interest, these medications likely operate through diverse neurochemical mechanisms, suggesting that combination therapy may be a rational next step that could increase treatment gains further in cocaine-dependent patients. The Medications Development Program has also identified multiple neuronal mechanisms that are altered by chronic administration of drugs of abuse. Advances in neuroscience have identified changes in conditioned cueing, drug priming, stress-induced increases in drug intake, and reduced frontal inhibitory mechanisms as all being possible for the development of, maintenance of, and possible relapse to, addiction. Potential medications that modulate these mechanisms are highlighted.

Monoaminergic ligands modified a naltrexone discriminative stimulus in rhesus monkeys dependent on 2 mg/kg per day of the mu opioid L-alpha-acetylmethadol (LAAM). This study examined a role for monoamines in the directly observable and physiologic manifestations of LAAM withdrawal induced by naltrexone in the same monkeys. The effects of saline, clonidine (0.032 mg/kg), haloperidol (0.032 mg/kg), cocaine (1.0 mg/kg), amphetamine (1.0 mg/kg) and imipramine (10.0 mg/kg) were examined in LAAM-dependent monkeys that subsequently received saline or naltrexone (0.0001-1.0 mg/kg). Naltrexone dose-dependently increased respiration, abdominal rigidity and salivation. Clonidine attenuated each of these withdrawal signs, whereas haloperidol increased some (i.e. respiration) and decreased others (i.e. salivation). When administered alone, cocaine and amphetamine increased respiration and also increased the respiratory stimulant effects of naltrexone; cocaine and amphetamine did not attenuate any measure of withdrawal. With the exception of a decrease in naltrexone-induced salivation, imipramine was without effect. These results are strikingly different from results in these same LAAM-dependent monkeys showing that cocaine and amphetamine, but not clonidine, markedly attenuated a naltrexone discriminative stimulus. That monoaminergic ligands differentially alter the directly observable and discriminative stimulus effects of naltrexone in LAAM-dependent monkeys supports the view that monoamines differentially mediate the physical manifestations (norepinephrine) and subjective experience (dopamine) of opioid withdrawal.

We examined the effects of prenatal exposure to the long acting opiate l-alpha-acetylmethadol (LAAM) followed by postnatal withdrawal on hypothalamic-pituitary-adrenal (HPA) axis reactivity in neonatal and adult rats and anxiety-like behavior in adult rats. Female rats were treated with LAAM (0, 0.2, or 1.0 mg/kg/day) via oral gavage for 28 days prior to and continuing throughout pregnancy. Pups were fostered at birth to nontreated, lactating dams and underwent opiate withdrawal. On postnatal day (PND) 18, prenatal opiate-exposed male and female rat pups displayed a decreased corticosterone response 2 h after the application of an immunological stressor and 15 min following a social stressor compared to controls. In contrast, in adulthood, prenatal opiate-treated rats showed a heightened corticosterone response compared to prenatal water-treated controls at 3 h, but not 8 h, following an immunological stressor. Males prenatally treated with 1.0 mg/kg LAAM displayed elevated startle responding compared to the other prenatally treated male groups, but there was no effect of prenatal treatment in females. There were no effects of prenatal treatment in the open field test in either sex. These results suggest that prenatal opiate exposure followed by postnatal withdrawal dysregulated the HPA axis response to stressors in the neonate and adult and differentially affected adult anxiety-like behavior in males and females.

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.

Efficacy is one determinant of whether a drug is an agonist or an antagonist under a particular set of conditions. Relative efficacy among the μ opioid receptor (MOR) ligands buprenorphine, nalbuphine, and morphine was examined in monkeys dependent on morphine (3.2 mg/kg/day) or l-α-acetylmethadol (LAAM) (1.0 mg/kg twice daily) and that discriminated naltrexone (0.0178 mg/kg) from saline. In morphine-treated monkeys, buprenorphine and not nalbuphine substituted for naltrexone. When administered before naltrexone in morphine-treated monkeys, morphine and nalbuphine shifted the naltrexone dose-effect curve to the right, while buprenorphine shifted the naltrexone dose-effect curve to the left. Under conditions of acute morphine deprivation, naltrexone-lever responding was slightly attenuated by buprenorphine and markedly attenuated by nalbuphine and morphine. In LAAM-treated monkeys, buprenorphine substituted completely for naltrexone in only one monkey, while nalbuphine and morphine failed to substitute in any monkey. When administered before naltrexone in LAAM-treated monkeys, buprenorphine, nalbuphine, and morphine dose dependently shifted the naltrexone dose-effect curve to the right, with the exception of one monkey in which buprenorphine shifted the naltrexone dose-effect curve to the left. These results demonstrate that a low efficacy MOR ligand can exert agonist or antagonist actions in the same animal depending on immediate pharmacologic history. The qualitatively different effects of buprenorphine in morphine- and LAAM-treated monkeys might be related to magnitude of dependence insofar as dependence can determine the efficacy required for agonist activity. Thus, buprenorphine has markedly different effects across different levels of opioid dependence.

Opiate withdrawal during pregnancy may occur because of voluntary or forced detoxification, or from rapid cycling associated with exposure to short-acting "street" opiates. Thus, animal modeling of prenatal withdrawal and development of potential therapeutic interventions is important. Direct developmental effects of opiates and/or withdrawal can be studied using a chick model. In ovo administration of the long-acting opiate N-desmethyl-l-alpha-noracetylmethadol (NLAAM) induces opiate dependence in the chick embryo. We examined activation of the hypothalamic-pituitary-adrenal (HPA) axis (assessed via serum corticosterone) and hemodynamic changes (assessed as changes in apparent diameter of vitelline (extraembryonic) blood vessels) after chronic NLAAM exposure and naloxone (Nx)-precipitated withdrawal during late stages of embryogenesis. Nx-precipitated withdrawal increased corticosterone 2- to 4.5-fold and diameters of vitelline blood vessels by 15 to 45%. NLAAM exposure itself did not effect these measures. In a second set of experiments, isobutylmethylxanthine (IBMX), a phosphodiesterase inhibitor, was injected into eggs with embryos. IBMX similarly increased corticosterone and vitelline vessel diameter, with a similar time course and response magnitude. Previous studies found that serotonin(2) (5-HT(2)) receptors were involved in other withdrawal manifestations, so we determined whether they were likewise involved. Pretreatment with the 5-HT(2) antagonist ritanserin completely blocked HPA axis activation and vasodilation associated with both Nx-precipitated withdrawal and IBMX administration. This indicates that 5-HT(2) receptors, directly or indirectly, mediate these withdrawal manifestations in the chick embryo.

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."

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.

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.

Incubation of l-α-acetylmethadol (LAAM) or norLAAM with cDNA-expressed P450s 3A4, 2B6, and 2C18 produced significant N-demethylation products. P450s 2C19, 2C8, 3A5, 2C9, 3A7, 1A1, and 2D6 (norLAAM only), also produced detectable product. Coexpression of cytochrome b5 enhanced LAAM N-demethylation, most dramatically for 3A4, but had marginal effects on norLAAM N-demethylation. Modeling total liver metabolism using immunoquantification and relative activity factors of P450s suggests contributions of P450 3A4 > 2B6 > 2C18, with the importance of 2B6 to 2C isozymes enhanced by relative activity factors. The ratio of dinorLAAM to norLAAM plus dinorLAAM formed from LAAM did not exceed 20%, and was isozyme and cytochrome b5 coexpression dependent. This ratio decreased with concentration with 3A4, but was relatively constant for 2B6 and 2C18. The human liver microsomes substrate-concentration response was similar to cDNA-expressed 3A4, but the ratio was higher. Changes in the environment of cDNA-expressed 3A4 also effected the magnitude of the ratio, but not the concentration-dependent decrease. These studies show that the N-demethylation of LAAM and norLAAM is not restricted to P450 3A4, particularly P450s 2B6 and 2C18, and suggest that the mechanism of sequential metabolism for 3A4 differs from that of 2B6 and 2C18.

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.

Long-acting opioid agonists methadone and l-α-acetylmethadol (LAAM) prevent withdrawal in opioid-dependent persons. Attempts to synthesize [(11)C]-methadone for PET evaluation of brain disposition were unsuccessful. Owing, however, to structural and pharmacologic similarities, we aimed to develop [(11)C]LAAM as a PET ligand to probe the brain exposure of long-lasting opioids in humans. This manuscript describes [(11)C]LAAM synthesis and its biodistribution in mice. The radiochemical synthetic strategy afforded high radiochemical yield, purity and specific activity, thereby making the synthesis adaptable to automated modules.

l-alpha-Acetylmethadol (LAAM) is approved as a substitute for methadone for the treatment of opiate addiction. Analytical methods are needed to quantitate LAAM and its two psychoactive metabolites, norLAAM and dinorLAAM, to support pharmacokinetic and other studies. We developed a gas chromatographic-positive ion chemical ionization-mass spectrometric method for these analyses. The method uses 0.5 mL urine or 1.0 mL plasma or tissue homogenate, deuterated (d3) isotopomers as internal standards, methanolic denaturation of protein (for plasma and tissue), and extraction of the buffered sample with n-butyl chloride. For tissue homogenates, an acidic back extraction is included. norLAAM and dinorLAAM were derivatized with trifluoroacetic anhydride. Chromatographic separation of LAAM and derivatized norLAAM and dinorLAAM is achieved with a 5% phenyl methylsilicone capillary column. Positive ion chemical ionization detection using methane-ammonia as the reagent gas produces abundant protonated ions (MH+) for LAAM (m/z 354) and LAAM-d3 (m/z 357) and ammonia adduct ions (MNH4+) for the derivatized norLAAM (m/z 453), norLAAM-d3 (m/z 45 6), dinorLAAM (m/z 439), and dinorLAAM-d3 (m/z 442). The linear range of the calibration curves were matrix dependent: 5-300 ng/mL for plasma, 10-1000 ng/mL for urine, and 10-600 ng/g for tissue homogenates. The low calibrator was the validated limit of quantitation for that matrix. The method is precise and accurate with percent coefficients of variation and percent of targets within 13%. The method was applied to the analysis of human urine and plasma samples; rat plasma, liver, and brain samples; and human liver microsomes following incubation with 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.

A method is described for the simultaneous determination of l-alpha-acetylmethadol (LAAM) and its N-demethylated metabolites, l-alpha-noracetylmethadol (norLAAM) and l-alpha-dinoracetylmethadol (dinorLAAM), in plasma by gas chromatography-chemical ionization mass spectrometry. Deuterated internal standards for each analyte serve as carriers and control for recovery during sample purification on a solid-phase extraction column (C18), and subsequent separation and analysis on a DB-17 capillary column. With this method, we have determined levels of LAAM, norLAAM, and dinorLAAM in small volumes of plasma (100 microliters). The limit of quantitation for all analytes was approximately 1.0 ng/g plasma and the limit of detection was approximately 0.5 ng/g plasma. An experimental application is also described where these analytes are quantitated in plasma obtained from rats before, during, and after chronic administration of LAAM-HCl. Since this technique affords a selective and sensitive means of detection of LAAM and its active, N-demethylated metabolites in small samples of blood, it may enable patient compliance to be more easily assessed by allowing samples to be collected by a simple finger-prick technique.

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.

Much is known about the immunomodulatory effects of opiate exposure and withdrawal in adult rats. However, little research has delved into understanding the immunological consequences of prenatal opiate exposure and postnatal withdrawal. The purpose of the current study was to measure changes in responding to immune stimulation in adult rats following prenatal opiate exposure. Further, we sought to characterize the role of interleukin (IL)-1beta in these changes. Following prenatal exposure to the long-acting opiate l-alpha-acetylmethadol (LAAM), adult male and female rats were assessed for their fever response to lipopolysaccharide (LPS). Blood and tissue samples were collected to measure circulating IL-1beta and IL-1beta protein in the hypothalamus and spleen. Prenatal LAAM exposure resulted in a blunted fever response to LPS injection without any changes in basal body temperature or in response to saline injection. Circulating IL-1beta was not affected by prenatal LAAM exposure, nor was IL-1beta protein in the spleen. Interestingly, mature IL-1beta protein was elevated in the hypothalamus of prenatally LAAM-treated rats. These results indicate that prenatal opiate exposure blunts the fever response of adult offspring. Direct action of IL-1beta is likely not the cause of the dysfunction reported here. However, alterations in signaling mechanisms downstream from IL-1beta may play a role in the altered fever response in adult rats treated prenatally with opiates.

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.

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.

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.

Objective: Levo-α-acetylmethadol (LAAM, levacetylmethadol) is a long-acting opioid agonist used for the prevention of opioid withdrawal. LAAM undergoes sequential N-demethylation to norLAAM and dinorLAAM, which are more potent and longer-acting than LAAM. Hepatic and intestinal microsomal N-demethylation in vitro is catalysed mainly by cytochrome P450 (CYP) 3A4; however, the role of CYP3A in LAAM disposition in humans in vivo is unknown. This investigation tested the hypothesis that CYP3A induction (or inhibition) would increase (or decrease) LAAM metabolism and bioactivation and, thus, clinical effects. It also related changes in LAAM disposition during enzyme inhibition or induction to any changes in pharmacological effect. Methods: Healthy volunteers (n = 13) completed the three-way, randomised, balanced crossover study. Subjects received oral LAAM (0.25 mg/kg) after CYP3A induction (rifampicin [rifampin]), inhibition (troleandomycin) or nothing (controls). Plasma and urine LAAM, norLAAM and dinorLAAM were determined by electrospray high-performance liquid chromatography/mass spectrometry (HPLC/MS). Dark-adapted pupil diameter change from baseline (miosis) was the LAAM effect measure. Results were analysed by noncompartmental methods and by a combined pharmacokinetic/pharmacodynamic model. Results: Compared with controls, CYP3A induction (or inhibition) decreased (or increased) plasma LAAM concentrations and mean area under the plasma concentration-time curve from time zero to infinity (AUC∞ 199 ± 91 [control] versus 11.3 ±4.0 [rifampicin] and 731 ±229 ng · h/mL [troleandomycin]; p < 0.05), and increased (or decreased) median formation clearances of norLAAM (1740 versus 14 100 and 302 mL/h/kg; p < 0.05) and dinorLAAM (636 versus 7840 and 173 mL/h/kg; p < 0.05). Surprisingly, however, CYP3A induction (or inhibition) decreased (or increased) mean plasma metabolite AUC from 0 to 96 hours (AUC96) [norLAAM + dinorLAAM] (859 ± 241 versus 107 ± 48 and 1185 ±179 ng · h/mL; p < 0.05) and clinical effects (mean miosis AUC96 128 ± 40 versus 22.5 ± 14.9 and 178 ± 81 mm · h; p < 0.05). Clinical effects were best correlated with plasma norLAAM concentrations. Conclusion: CYP3A mediates human LAAM N-demethylation and bioactivation to norLAAM and dinorLAAM in vivo. Paradoxically, however, CYP3A induction decreased and inhibition increased LAAM active metabolite concentrations and clinical effects. This suggests a CYP3A-mediated metabolic pathway leading to inactive metabolites, which predominates over CYP3A-dependent bioactivation. These results highlight the need for clinical investigations to validate in vitro drug metabolism studies.

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 mechanism responsible for decreased opioid use during opioid substitution therapy is not fully understood. To examine whether l-alpha-acetylmethadol (LAAM) or buprenorphine attenuate behavioral effects of opioids through cross-tolerance, discriminative stimulus effects of high and low efficacy mu agonists were examined following 3- or 7-day treatment with LAAM or buprenorphine in pigeons discriminating between saline and heroin or between saline and buprenorphine, respectively. Heroin, buprenorphine and nalbuphine occasioned high levels of drug-appropriate responding in both groups; kappa opioids and non-opioids occasioned predominantly saline-appropriate responding. Administration of LAAM (3.2 mg/kg) or buprenorphine (3.2 mg/kg) occasioned predominantly heroin- or buprenorphine-appropriate responding, respectively. After discontinuation of LAAM treatment, the potency in occasioning heroin-key responding was markedly decreased for nalbuphine, slightly decreased for buprenorphine, and unchanged for heroin. Following discontinuation of buprenorphine treatment, the potency in occasioning buprenorphine-key responding was decreased for nalbuphine and unchanged for buprenorphine and heroin. Thus, greater cross-tolerance developed from LAAM and buprenorphine to low efficacy mu agonists as compared to a higher efficacy agonist. Failure of LAAM and buprenorphine treatment to modify the effects of heroin, under conditions that attenuate the effects of lower efficacy mu opioids, provides a possible rationale for why heroin abuse persists in some patients receiving large doses of agonists in substitution therapy.

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.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 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.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.