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One group of six male control rats [21 months old] and one group of six male rats of the same age, singularly stored in a cage, and treated with acetyl-l-carnitine-HCl (ALCAR: 60 mg/kg/day/p.o.) for six months were tested in the spatial learning/memory Morris maze-water task and for atrophy and cell loss in seven myelo- and cytostructurally defined basal forebrain (BF) cholinergic regions [Gritti et al., 1993 J Comp Neurol 329: 438-457]. Coronal sections 25 mum thick were cut through the BF regions and processed every 200 mum for choline acetyltransferase (ChAT) immunohistochemistry. The ALCAR-treated rats had significantly shorter exit times on the Morris maze-water task test than the control rats (ANOVA-enzyme: F(1,39)=112.5, P=0.0001; sessions: F(3,39)=10.41, P=0.0001; interaction: F(3,39)=5.09, P=0.0044). Degenerative morphological changes in the BF ChAT-positive cells were observed in the control rats, but not in the treated animals, in: the diagonal band of Broca, the magnocellular preoptic nucleus, the olfactory tubercle, the substantia innominata, and the globus pallidus (ANOVA-enzyme: F(1,2)=14, P=0,0003; structures: F(6,7)=4, P=0,0018; interaction: F(6,7)=3, P=0,0043). In the diagonal band of Broca (P<0.0494) and in the magnocellular preoptic nucleus (P<0.0117) there were significantly fewer ChAT-positive neurons in the aged control rats than in the ALCAR-treated rats. These results demonstrate that in rats aged from 15 to 21 months ALCAR treatment significantly attenuated spatial learning/memory impairment on the Morris maze-water task and also importantly reduced the degeneration in size and number of cholinergic cells in the BF.

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 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.

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.

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<0.01) with a significant increase in the M3G/M6G ratio (P<0.01) for all compounds tested. Detailed analysis with (R)- and (S)-methadone revealed noncompetitive inhibition with (R)-methadone Ki of 320+/-42 microm and 192+/-12 microm for M3G and M6G, respectively, and (S)-methadone Ki of 226+/-30 microm and 152+/-20 microm for M3G and M6G, respectively. Ki values for M3G inhibition were significantly greater than for M6G for (R)-methadone (P=0.017, 128; 55, 202 microm) and (S)-methadone (P=0.026, 75; 22, 128 microm)., Conclusions: Both methadone enantiomers noncompetitively inhibited the formation of morphine's primary metabolites, with greater inhibition of M6G formation compared with M3G. These findings indicate a mechanism for reduced morphine clearance in methadone-maintained patients and reduced relative formation of the opioid active M6G compared with M3G.

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.

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., (Copyright 2005 APA, all rights reserved.)

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.

Efficacy is one determinant of whether a drug is an agonist or an antagonist under a particular set of conditions. Relative efficacy among the micro opioid receptor (MOR) ligands buprenorphine, nalbuphine, and morphine was examined in monkeys dependent on morphine (3.2 mg/kg/day) or l-alpha-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.

l-alpha-acetylmethadol is a long-acting narcotic analgesic that is used in the treatment of opiate addiction. However, the drug has been associated with cases of QT interval prolongation and ventricular arrhythmia. To understand the mechanism underlying these clinical findings, we examined the effects of l-alpha-acetylmethadol on the cloned human cardiac K(+) channels HERG (human ether-a-go-go-related gene), KvLQT1/minK and Kv4.3. Using patch clamp electrophysiology, we found that l-alpha-acetylmethadol inhibited HERG channel currents in a voltage-dependent manner displaying an IC(50) value of 3 microM. The major active metabolite of l-alpha-acetylmethadol, noracetylmethadol, inhibited HERG with an estimated IC(50) values of 12 microM. l-alpha-acetylmethadol had little or no effect on Kv4.3 or KvLQT1/minK K(+) channel currents at concentration up to 10 microM. We conclude that the proarrhythmic effects of l-alpha-acetylmethadol are due to specific blockade of the HERG cardiac K(+) channel and that its active metabolite noracetylmethadol may provide a safer alternative in the treatment of opiate addiction.

We have evaluated the ability of various opioid agonists, including methadone, L-alpha-acetylmethadol (LAAM), fentanyl, meperidine, codeine, morphine, and buprenorphine, to block the cardiac human ether-a-go-go-related gene (HERG) K(+) current (I(HERG)) in human cells stably transfected with the HERG potassium channel gene. Our results show that LAAM, methadone, fentanyl, and buprenorphine were effective inhibitors of I(HERG), with IC(50) values in the 1 to 10 microM range. The other drugs tested were far less potent with respect to I(HERG) inhibition. Compared with the reported maximal plasma concentration (C(max)) after administration of therapeutic doses of these drugs, the ratio of IC(50)/C(max) was highest for codeine and morphine (>455 and >400, respectively), thereby indicating that these drugs have the widest margin of safety (of the compounds tested) with respect to blockade of I(HERG). In contrast, the lowest ratios of IC(50)/C(max) were observed for LAAM and methadone (2.2 and 2.7, respectively). Further investigation showed that methadone block of I(HERG) was rapid, with steady-state inhibition achieved within 1 s when applied at its IC(50) concentration (10 microM) for I(HERG) block. Results from "envelope of tails" tests suggest that the majority of block occurred when the channels were in the open and/or inactivated states, although approximately 10% of the available HERG K(+) channels were apparently blocked in a closed state. Similar results were obtained for LAAM. These results demonstrate that LAAM and methadone can block I(HERG) in transfected cells at clinically relevant concentrations, thereby providing a plausible mechanism for the adverse cardiac effects observed in some patients receiving LAAM or methadone.

Rationale: LAAM (alpha- l-acetylmethadol) is a derivative of the synthetic mu-opiate agonist methadone and is one of the four isomers of acetylmethadol. Methadone and LAAM have similar pharmacological properties and both are approved medications for the treatment of heroin dependency disorders. Few studies have reported on the pharmacology of acetylmethadol's other isomers and most of these have focused on their potential analgesic activity., Objectives: The purpose of the present investigation was to examine the discriminative stimulus effects of LAAM, the other isomers of acetylmethadol, and methadone in rats trained to discriminate heroin from water, and to compare the duration of the discriminative stimulus effects of heroin, methadone, and LAAM., Methods: Long-Evans rats were trained to discriminate 0.3 mg/kg heroin from water under a fixed ratio 10 (FR10) schedule of food reinforcement. Dose-response functions for heroin, methadone, LAAM, three other isomers of acetylmethadol: alpha- d-acetylmethadol, beta- d-acetylmethadol, beta- l-acetylmethadol, and its precursor, beta- l-methadol were examined. Additionally, the time course effects for heroin, methadone, and LAAM were examined., Results: LAAM and methadone dose-dependently occasioned heroin-like discriminative stimulus effects. Two of acetylmethadol's isomers, alpha- d-acetylmethadol and beta- d-acetylmethadol, were more potent than LAAM in producing heroin-like effects. The beta- l-methadol precursor and beta- l-acetylmethadol did not fully substitute for heroin's discriminative stimulus. LAAM elicited heroin-like discriminative stimulus effects for at least 6 h and generated partial generalization up to 36 h following administration., Conclusions: Methadone, LAAM, beta- d-acetylmethadol and alpha- d-acetylmethadol, but not beta- l-acetylmethadol and beta- l-methadol evoke heroin-like discriminative stimulus effects.

Two new long-acting opioid agonists have recently been introduced for the substitutional treatment of opioid-dependent patients: Orlaam (LAAM) and Subutex (buprenorphine). Both have a dose-related duration of action two to three times that of methadone, and can be given only three times a week instead of daily, thus reducing the need for take-home doses. Further, the longer duration of action provides a smoother blood level with fewer fluctuations between doses. With the availability of buprenorphine and LAAM as alternatives to methadone, agonist treatment can be more differentiated, and one can hope that this will increase the quality of the treatment.

The development and approval of levo-alpha-acetylmethadol (LAAM) as a pharmacotherapeutic agent in opioid agonist therapy provided an alternative to methadone. Clinicians recognized the potential benefits that LAAM, a synthetic mu agonist with pharmacological properties which differ from those of methadone,could have in the treatment management of addicts in opioid agonist therapy. We report our experience utilizing LAAM from 1995 to 1999 at the Hines VA opioid agonist therapy clinic. The addition of LAAM to the clinic's treatment armamentarium has resulted in management options that have improved the areas of patient recruitment, patient retention, patient traffic, take-home medication, detoxification, and treatment outcomes.

Although l-alpha-acetylmethadol (LAAM) is a maintenance treatment for opioid dependence, few studies have systematically assessed the behavioral effects of LAAM and other drugs in LAAM-treated subjects. In the current study, we assessed the ventilatory, antinociceptive, and rate-decreasing effects of drugs (s.c. except dynorphin, which was administered i.v.) in rhesus monkeys (n = 3 or 4) before and during chronic treatment with 1.0 mg/kg/12 h LAAM (s.c.). Minute volume (V(E)) was reduced to 62% of baseline during LAAM treatment and remained depressed after more than 10 months of LAAM treatment. A cumulative dose of 10.0 mg/kg morphine decreased V(E) to similar values under baseline (53%) and LAAM-treated (52%) conditions; however, larger doses of morphine (up to 56.0 mg/kg) could be administered safely to LAAM-treated monkeys. LAAM treatment produced dependence as evidenced by a 220% increase in V(E) after a dose of naltrexone (0.032 mg/kg) that did not modify ventilation under baseline conditions. Compared with baseline, LAAM treatment increased the ED(50) values for the rate-decreasing effects of nalbuphine, morphine, and alfentanil by 7-, 7-, and 2-fold, respectively, in monkeys responding under a fixed ratio 10 schedule of food presentation. Similarly, LAAM treatment increased ED(50) values for the antinociceptive effects of morphine and alfentanil by 5- and 3-fold, respectively. LAAM treatment also increased the ED(50) values for the antinociceptive effects of the kappa-agonist enadoline by 5-fold and not those of U-50,488. That tolerance developed differentially to the ventilatory, rate, and antinociceptive effects of mu-agonists in LAAM-treated monkeys suggests that cross-tolerance might not be a safe therapeutic approach for the treatment of some opioid abusers.

levo-alpha-Acetylmethadol (LAAM) and methadone are full mu-opioid agonists used to treat opioid dependence. Current labeling indicates that LAAM is less potent than methadone. Clinical studies have not determined the relative potency of these drugs. This study compared the effects of acute doses of LAAM and methadone and also examined the ability of naloxone to reverse their effects. Five occasional opioid users received once weekly doses of either placebo, LAAM, or methadone (15, 30, or 60 mg/70 kg p.o.) in agonist exposure sessions and then received naloxone (1.0 mg/70 kg i.m.) 24, 72, and 144 h after agonist exposure. Subject-rated, observer-rated, and physiological measures were assessed regularly. Comparisons of physiological and subjective measures collected in agonist exposure sessions indicate that LAAM is not less potent than methadone under acute dosing conditions. For some measures, LAAM was significantly more potent. Three subjects who entered the study were withdrawn for safety reasons due to greater than anticipated and clinically relevant respiratory depression after receiving 60 mg of LAAM. Naloxone did not fully reverse the pupil constriction produced by 60 mg of LAAM. Acute agonist effects suggest that LAAM may be more potent than methadone and more potent than current labeling indicates. An accurate LAAM:methadone relative potency estimate will aid determination of adequate doses for opioid-dependent patients inducted onto LAAM and for methadone maintenance patients who choose to switch to more convenient thrice-weekly LAAM.

This study characterized discriminative stimulus and other effects of naltrexone in rhesus monkeys treated daily with the long-acting opioid l-alpha acetylmethadol (LAAM). An initial dose-finding study assessed the rate-decreasing effects of naltrexone in three monkeys receiving LAAM daily (0.32-1.78 mg/kg); subsequently, these monkeys and a fourth received 1.0 mg/kg/12 hr of LAAM although discriminating between naltrexone and saline. Responding occurred on the saline lever after the administration of LAAM, whereas >90% drug-lever responding occurred after the administration of 0.1 mg/kg of naltrexone that also elicited signs of withdrawal. Naloxone and quadazocine, but not morphine, nalbuphine or ketamine, substituted for naltrexone. Morphine and nalbuphine shifted the naltrexone dose-effect curve to the right. Compared to precipitated withdrawal, deprivation-induced withdrawal occasioned less naltrexone-lever responding and fewer observable signs of withdrawal. Maximal naltrexone-level responding occurred 24 to 48 hr after the discontinuation of LAAM treatment; the frequency of other withdrawal signs also peaked 24 to 48 hr after the discontinuation of LAAM. Partial naltrexone-lever responding occurred for up to 10 days after discontinuation of LAAM treatment; 4 and 8 days after the discontinuation of LAAM treatment, 0.1 mg/kg of naltrexone did no further increase naltrexone-lever responding or withdrawal signs suggesting that less-then-maximal naltrexone-lever responding was not due to long-lasting effects of LAAM or its metabolites. The discriminative stimuli that are associated with LAAM deprivation might be different from the stimuli associated with either training condition. This study is the first antagonist discrimination in non-humans primates treated chronically with LAAM and the results indicate that the naltrexone stimulus is related to opioid withdrawal.

Levo-alpha-acetylmethadol (LAAM) currently is approved as an opioid maintenance treatment. This double-blind study was designed to characterize withdrawal suppression and opioid blockade produced by two different LAAM maintenance doses. Outpatient opioid-dependent volunteers were stabilized (5-7 weeks) on 25 (n = 8) or 75 mg (n = 8) LAAM administered every-other-day with placebo administered on intervening days. After stabilization, four inpatient, randomly ordered experimental sessions were conducted at 24, 48, 72 and 96 hr after LAAM dosing; the timing of these sessions corresponds to intervals that occur during typical thrice-weekly treatment and after a missed dose. During each session, after baseline assessments, ascending doses of hydromorphone (0, 6 and 12 mg i.m.) were administered 45 min apart; physiological, subjective and observer-rated effects were recorded throughout the session. Physiological and subjective indices of opioid withdrawal measured at session base lines increased with time since the last LAAM dose, but did not depend on the maintenance dose. Withdrawal symptoms were mild in both groups, even at 96 hr after LAAM dosing. Hydromorphone produced dose-related opioid agonist effects at all intervals in the 25 mg LAAM group; these effects were attenuated substantially in the 75 mg LAAM group. Time since last LAAM dose had little influence on hydromorphone effects in either group. Thus, 75 mg LAAM provides opioid blockade and withdrawal suppression for up to 96 hr, whereas 25 mg LAAM is relatively ineffective at producing significant opioid blockade.

Levo-alpha-acetylmethadol (LAAM) is a long-acting opioid agonist approved for use as a maintenance treatment for opioid dependence. Previous clinical studies report that the onset of the effects of LAAM is slower after parenteral administration than oral administration; however, preclinical studies suggest otherwise. This study examined the pharmacodynamic and pharmacokinetic profile of LAAM when given orally and intravenously to humans. Opioid-experienced volunteers (n = 6), who were not physically dependent on opioids, received LAAM (20 and 40 mg/70 kg i.v. and p.o.) and placebo under double-blind, double-dummy conditions during five weekly experimental sessions. Behavioral, physiological, subjective and pharmacokinetic measures were collected before and for 96 hr after drug administration. Intravenous LAAM produced significant subjective and physiological effects that appeared within 5 min, whereas the effects of oral LAAM appeared more slowly within 1 to 2 hr after drug administration. Pharmacokinetic data indicate that the immediate effects of intravenous LAAM are largely attributable to the parent drug rather than the active metabolites, nor-LAAM and dinor-LAAM. LAAM produced prototypic opioid agonist effects (i.e., miosis, subjective ratings of high, nodding) that were of equal magnitude across routes, dose-related and of long duration (up to 60 hr). These data are in contrast to previous clinical reports and indicate that LAAM produces effects of immediate onset when administered parenterally, which suggests that intravenous LAAM possesses greater abuse potential than previously believed.

l-alpha-Acetyl-N-normethadol (nor-LAAM) and l-alpha-acetyl-N, N-dinormethadol (dinor-LAAM) are active metabolites of the opiate l-alpha-acetylmethadol (LAAM), and they contribute to the prolonged actions of the parent compound. Single doses of nor-LAAM, dinor-LAAM, LAAM, methadone and morphine were given intravenously to the chronic spinal dog to determine acute, single-dose effects and their ability to suppress withdrawal in morphine-dependent dogs. These opioids produced dose-dependent antinociception, decreases in body temperature and pupillary constriction. For these measures, dinor-LAAM was 1.5 to 3 times and nor-LAAM 6 to 12 times as potent as LAAM. Five hours after the acute administration of LAAM or either of the metabolites, a 1-mg/kg dose of naltrexone given intravenously produced withdrawal, indicating the presence of acute physical dependence. In dogs physically dependent on a daily dose of 125 mg of morphine, nor-LAAM was 9 times as potent as either LAAM or dinor-LAAM in suppressing spontaneous withdrawal 40 hr after the last dose of morphine. The efficacies of LAAM and its demethylated metabolites in the dog for producing acute opiate effects were comparable with those of morphine and methadone. There was a trend, however, for LAAM to suppress the expression of abstinence more fully than either metabolite. The usefulness of LAAM as a treatment for opiate addiction is likely due in part to the equivalent efficacies and higher potencies of its nor and dinor metabolites.

The discriminative stimulus effects of l-alpha-acetylmethadol (LAAM), l-alpha-acetylnormethadol (nor-LAAM), l-alpha-acetyldinormethadol (dinor-LAAM), buprenorphine and methadone were investigated in morphine-treated (3.2 mg/kg/day) rhesus monkeys (n = 3-6) discriminating between saline and naltrexone (0.01 mg/kg) and responding under a fixed ratio (FR) schedule of stimulus-shock termination. Monkeys responded on the naltrexone lever after either the administration of 0.01 mg/kg of naltrexone or the substitution of saline for the daily dose of morphine (i.e., 27-hr morphine deprived). Morphine dose-dependently reversed naltrexone lever responding in morphine-deprived monkeys. Methadone, LAAM, nor-LAAM and dinor-LAAM had morphine-like discriminative stimulus effects in all monkeys, whereas, buprenorphine had naltrexone-like discriminative stimulus effects in three monkeys and morphine-like effects in two monkeys; 24 hr after administration, buprenorphine antagonized the effects of morphine in the former and antagonized the effects of naltrexone in the latter. The agonist and antagonist effects of buprenorphine persisted for more than 6 days. The relative duration of action was: buprenorphine > LAAM > nor-LAAM = methadone = dinor-LAAM = morphine. That buprenorphine had markedly different discriminative stimulus effects in monkeys treated identically with morphine is likely due to the low efficacy of buprenorphine and emphasizes the difficulty in predicting the behavioral effects of buprenorphine in opioid-dependent individuals. The considerably longer duration of LAAM, than either nor-LAAM or dinor-LAAM, indicates that the rate of metabolite formation is important for the long duration of LAAM and further suggests that variations in metabolic activity among individuals might result in differences in the behavioral effects of LAAM.

The purpose of this study was to examine the effects of acute and chronic treatment with l-alpha-acetylmethadol (LAAM), a long-acting mu opioid agonist that is used to treat opioid dependence. In pigeons responding under an FR20 schedule of food presentation, LAAM decreased responding in a dose- and time-dependent manner, with the largest decrease occurring 4 hr after the administration of 5.6 mg/kg. Acute (1.0-5.6 mg/kg) or chronic (1.0-5.6 mg/kg/day) treatment with LAAM decreased sensitivity to morphine and increased sensitivity to naltrexone, although for both drugs changes in sensitivity were 3- to 10-fold greater during chronic treatment. Chronic LAAM treatment (5.6 mg/kg/day) also decreased sensitivity to fentanyl and etonitazene by 3-fold and increased sensitivity to nalorphine and nalbuphine by 30- and 6-fold, respectively; sensitivity to enadoline and ketamine increased only 2- to 3-fold. When LAAM treatment was temporarily suspended for 1 day, response rates decreased to 33% of control; this disruption was reversed by acute administration of morphine or etonitazene. Increased sensitivity to naltrexone and disruptions in responding when LAAM treatment was temporarily suspended indicate that dependence developed to LAAM. Tolerance and cross-tolerance to agonists as well as increased sensitivity to antagonists can be similar during chronic treatment with morphine or LAAM; however, increased sensitivity to nalbuphine during LAAM treatment is not typically observed during morphine treatment, suggesting that dependence on LAAM might not be identical to dependence on morphine. Finally, changes in sensitivity to other drugs might predict altered sensitivities to opioids and nonopioids in humans receiving LAAM.

The efficacy and cost-effectiveness of opioid substitution therapy for the treatment of opioid addiction has been well documented within the methadone maintenance model for over thirty years. However, methadone does not meet the specific treatment needs of all opioid-dependent persons who might benefit from substitution therapy; consequently, a significant proportion of heroin addicts remain untreated. The recent approval of l-alpha-acetylmethadol (LAAM) as a maintenance treatment agent represents the first opioid substitution alternative to methadone. LAAM is a fundamentally different medication than methadone, with unique pharmacological characteristics. Its use requires a different approach to the clinical management of opioid substitution therapy and a different medication delivery strategy. The availability of LAAM has potential important implications for patients, clinics, and the community at large. Full realization of its advantages could move opioid substitution therapy into mainstream medical care and draw into treatment a substantial number of new patients able to benefit from such treatment. Buprenorphine, the other new opioid substitution therapy under development, shares some common advantages with LAAM. Its high safety profile and low physical dependence liability make it uniquely suitable for a subset of addicts as well as an initial treatment of choice in the opioid substitution treatment armamentarium.

Administration of morphine sulfate to rhesus monkeys may activate the quiescent lymphocyte for proliferation, induce a transient increase in the T cell proliferative response to mitogens, and cause an enhanced interleukin-2 release from the mitogen-stimulated lymphocytes. However, longitudinal studies of the animals dependent upon morphine or L-a-acetyl-methadol, a long-acting opioid, revealed an overall immunosuppression of T helper functions. In vitro studies using morphine and its antagonist naloxone suggested that the immunosuppression was not a result of a direct interaction between the opioids and conventional opiate receptors which might have been present on the lymphocytes. The studies also showed the importance of measuring [3H]thymidine incorporation rather than its uptake into cells to assess T cell activation.

Cardiac muscle contractile responses to six narcotic analgesics (morphine, meperidine, pentazocine, fentanyl, methadone and l-alpha-acetylmethadol), at concentrations from 10(-8) to 10(-4) M, both in the presence and absence of the narcotic antagonist, naloxone, were studied in the isolated, isometric cat right ventricular papillary muscle preparation. Measurements of maximum developed tension (T), maximum rate of tension development (dT/dt) and time to peak tension indicated that no major changes in contractile function occurred with any narcotic at concentrations of 10(-8) to 10(-6) M except for small but significant (P < .05) increases in all three parameters at 10(-6) M fentanyl, and small but significant increases in dT/dt at 10(-8) to 10(-6) M meperidine. At 10(-5) M narcotic, dT/dt was significantly elevated in meperidine-treated muscles (+7%), but significantly reduced in muscles exposed to pentazocine (-8%) or l-alpha-acetylmethadol (-11%). For all six narcotics, the 10(-4) M drug concentration resulted in depression of contractile function that was often associated with nonresponsiveness to electrical stimulation. Pretreatment of muscles with naloxone (10(-4) M) did not prevent this reduction of contractile performance except at the highest concentration (10(-4) M) of meperidine. Following removal of drug, contractile performance improved to varying degrees (recovery to 72-97% of control T), except in l-alpha-acetylmethadol-treated muscles, in which there was no recovery of T. Isoproterenol (0.8 X 10(-7) M) elicited a positive inotropic response whether administered in the presence of 10(-4) M narcotic or following narcotic removal. We conclude that narcotic analgesics in high concentrations exert a direct myocardial depressant effect which is not prevented by naloxone and therefore is not mediated by interaction with opiate receptors. Rather, several effects, including myocardial depression, its reversibility by both drug removal and isoproterenol and decreased muscle excitability are consistent with the hypothesis that narcotic analgesics in high concentrations exert nonspecific, local anesthetic effect on the myocardium.

The purpose of the study was to assess and compare EEG and behavioral correlates of abstinence from morphine, methadone, LAAM, NLAAM, and DNLAAM in dependent rats. Rats were initially trained to lever press for self-injections on a FR-20 schedule of reinforcement. Following substitution of saline for each of the narcotic agonists. REM sleep was significantly suppressed during morphine, methadone, and NLAAM abstinence, but not during LAAM and DNLAAM abstinence. Significant increases in lever pressing for saline during abstinence from morphine, methadone, and NLAAM emerged earlier than with LAAM and DNLAAM. Significant increases in head-shake behavior occurred during morphine, methadone, NLAAM, and DNLAAM abstinence, but not during LAAM abstinence. These results demonstrated further pharmacodynamic differences between the five narcotics studied. Our findings suggested that in dependent rats abstinence from LAAM was the least severe when compared with abstinence from any of the other four narcotic studied.

New N-propargyl analogs of SKF-525A and acetyl methadol were tested for their inhibitory potency toward P-450 multifunctional oxidase. Metabolism of these analogs appears to be different from the metabolism of SKF-525 A itself; no N-dealkylated species were detected, --in vitro N-demethylation of aminopyrine and spectrofluorometric measurements support the hypothesis of an interaction between the hepatic flavo-protein and the acetylenic function of the inhibitors.

1-Alpha-acetylmethadol (LAAM) maintenance treatment has been proposed as a favorable alternative to methadone maintenance. With an unobtrusive actometer we recorded two successive 24-h cycles of spontaneous motor activity from 12 patients receiving LAAM every other day, and from five receiving methadone every day. LAAM patients were about 50% more active on days of drug administration than on no-dose days (P less than 0.001). There were no significant day-to-day differences in motility of methadone patients. LAAM administered every other day may significantly modify the human circadian rhythm of spontaneous motility; further research is thus needed before this treatment is widely adopted.

Outpatients receiving daily methadone-maintenance treatment were crossed over to alternating-day doses of 1-alpha-acetylmethadol, receiving placebo on between-dose days. Spontaneous motility was dramatically higher on acetylmethadol dose days than on placebo days; activity on methadone days was intermediate between these extremes. Patients reported less vigor, more fatigue, and fewer ejaculations on placebo days than on acetylmethadol days, and patients' mood while on this drug was slightly euphoric in comparison to methadone. These effects are subtle, but such drug-induced variations in day-to-day behavior might adversely affect social interactions.

The microsomal cytochromes P-450 and b5 and the enzymes of the hepatic microsomal electron transport system (HMETS) including NADPH-cytochrome c reductase and NADPH oxidase activities were monitored in male ICR mice (25-30 g) over a six-day period following the repeated oral administration of 7, 14 and 28 mg/kg per day of l-alpha-acetylmethadol hydrochloride (LAAM) or an equivalent volume of water. Cytochrome P-450 and the microsomal enzyme activity of NADPH oxidase were maximally elevated (three- to four-fold above control values) by the third day of LAAM administration (28 mg/kg per day). These elevations not only correlated on a dose and a temporal basis with previously reported microsomal activities including LAAM N-demethylase, but also with the reported development of cellular tolerance and physical dependence following an identical regimen of LAAM. In addition, NADPH-cytochrome c reductase and cytochrome b5 increased in activity and content, respectively, after the repeated administration of this narcotic. However, the enzyme activity was first significantly elevated after only a single dose of LAAM. Thereafter, it showed a pattern of induction similar to that of NADPH oxidase. In contrast, cytochrome b5 was only elevated after the last repeated dose. The significance of these findings is discussed in some detail relative to the generation of the two analgesically active metabolites of LAAM.

Behavioral effects and blood or plasma levels of d-amphetamine, ethanol, cocaine, and diazepam were examined in rhesus monkeys treated chronically with alpha-l-acetylmethadol (LAAM), methadone, or vehicle. Chronic treatment with the opiates failed to alter blood or plasma levels and behavioral effects of d-amphetamine or ethanol. LAAM-maintained monkeys were somewhat less sensitive to rate-decreasing effects of cocaine on schedule-controlled responding, but cocaine plasma levels and half-lives generally did not differ across the chronic treatment conditions. Behavioral depression after diazepam was prolonged substantially in LAAM- and methadone-maintained monkeys, but blood levels of diazepam and metabolites were not increased prolonged in those animals. Naloxone partially antagonized the residual depression LAAM- and methadone-maintained monkeys 24 hr after diazepam, but had no effect on the weaker sesidual depression in vehicle-maintained aniamals. Thus, diazepam appeared to interfere with the metabolic inactivation of the opiates. One LAAM-maintained monkey showed recurrent episodes of LAAM overdose and eventually died during the course of the study.

l-alpha-Acetylmethadol (LAAM) was administered to lactating rat dams, and subsequent effects on hepatic drug-metabolizing enzymes of their offspring were assessed. Dams were given LAAM or a control solution in their drinking water following parturition and throughout lactation. Hepatic ethylmorphine-N-demethylase (EMDM) and aniline hydroxylase (AH) activities, as well as cytochrome P-450 content, were determined in the offspring at 21-23 days of age, or following sexual maturation (61-64 days). LAAM induced AH and EMDM activities, as well as cytochrome P-450 content in both male and female 21-23-day-old pups compared to controls; these differences were not observed at 61-64 days of age. In addition, normal sex-related differences in EMDM activity were apparent at 61-64 days of age. These results demonstrate the LAAM administration to lactating dams causes hepatic metabolic induction in the sexually immature rat, suggesting that LAAM and/or its metabolites passed to the pups via the milk. These changes, induced by LAAM administered via lactation, are reversible and do not interfere with the normal development of sex-dependent differences in hepatic EMDM activity observed in rats following sexual maturation.

A sensitive and specific radioimmunoassay has been developed which allows quantitation of picogram amounts of alpha-l-acetylmethadol (LAAM) in biological fluids without prior extraction. Antiserum was obtained from rabbits immunized with antigen prepared by conjugation of alpha-l-methadol hemisuccinate with thyroglobulin. The antiserum was stereospecific, distinguishing LAAM from its three stereoisomers. In addition, there was little cross-reaction in the assay by metabolites of LAAM and no interference with the assay by other narcotic analgesics. The sensitivity of the assay was 50 pg, requiring serum sample sizes as small as 10 microliters. The radioimmunoassay was used to determine serum concentrations of LAAM in five female dogs receiving i.v. injections of 2 mg/kg of LAAM. The decay of LAAM in serum appeared to be multiexponential, with a mean terminal half-life of 35 hr. The dogs were behaviorally depressed for at least 9 hr and hypothermic for at least 24 hr after injection. The persistence of these pharmacological effects was probably due to the slow elimination of LAAM and the presence of major metabolites which are pharmacologically active.

Rats maintained dependence by the self-administration of LAAM or morphine. Following the substitution of saline for LAAM, REM sleep was not disrupted, and the frequency of lever pressing for saline self-injections peaked at about 24 hr. In contrast, following the substitution of saline for morphine, REM sleep was suppressed for 24 hr while the frequency of lever pressing for saline self-injections peaked within 8 hr. When abstinence was induced by hourly iv naloxone injections, REM sleep occurrences were suppressed to a similar degree and for similar durations during naloxone-induced abstinence from both morphine and LAAM. These results suggest that the level of physical dependence maintained during self-administration of LAAM and morphine was similar. The relatively mild abstinence syndrome that was seen during saline substitution in LAAM-dependent rats was most likely related to the long plasma half-lives of the pharmacologically active N-demethylated metabolites of LAAM.

1-alpha-Acetylmethadol (LAAM), 1.4 mg/kg or greater, decreased the response of the cat nictitating membrane to pre- and postganglionic sympathetic nerve stimulation. LAAM had a greater effect on the low-frequency (0.5 Hz) than on the high-frequency (5-20 Hz) responses. No difference was observed between the effects of LAAM on the pre- as opposed to the postganglionic responses. The responses ot the nictitating membranes to intravenous epinephrine were not affected by LAAM. LAAM appears to act at the nerve terminal. The minimum dose of LAAM (1.4 mg/kg) which decreased the nictitating membrane responses also decreased blood pressure and heart rate. Naltrexone, 300 micrograms/kg, s.c., antagonized the effects of LAAM on the nictitating membrane responses and the cardiovascular actions of the drug. In anesthetized dogs, naltrexone completely blocked the blood pressure response to LAAM and partially blocked the effects of LAAM on heart rate and contractile force. The data suggest that LAAM may produce its cardiovascular effects, in part, by an action on the peripheral sympathetic nervous system which involves opiate binding sites. LAAM also appears to have direct actions on the heart to decrease heart rate and contractile force that do not involve opiate binding sites.

Male and female Wistar rats were administered alpha-1-acetylmethadol via their drinking water for one to two weeks. Hepatic aryl hydrocarbon hydroxylase, cytochrome P-450 and epoxide hydrase activities were measured after various doses of this drug. In female rats, a significant increase in aryl hydrocarbon hydroxylase and cytochrome P-450 occurred at doses as low as 4.7 mg/Kg/day. However, no change in epoxide hydrase activity occurred. In male rats, a significant increase in epoxide hydrase activity occurred at all doses tested. From these results, it is concluded that alpha-1-acetylmethadol induces a number of hepatic drug metabolizing enzyme systems.