[Anhedonia, depression, anxiety, and craving in opioid dependent patients stabilized on oral naltrexone or naltrexone implant]. / Angedoniia, depressiia, trevoga i vlechenie k upotrebleniiu narkotikov u patsientov s opioidnoi zavisimost'iu pri kursovom lechenii peroral'noi ili implantiruemoi formoi naltreksona.

AIM: To assess the relationship between long-term naltrexone treatment and anxiety, depression and craving in opioid dependent individuals. MATERIAL AND METHODS: Opioid dependent patients (n=306) were enrolled in a three cell (102ss/cell) randomized, double blind, double dummy, placebo-controlled 6-month trial comparing extended release implantable naltrexone with oral naltrexone and placebo (oral and implant). Monthly assessments of affective responses used a Visual Analog Scale for opioid craving, the Beck Depression Inventory, Spielberger Anxiety Inventory, and the Ferguson and Chapman Anhedonia Scales. Between-group outcomes were analyzed using mixed model analysis of variance (Mixed ANOVA) and repeated measures and the post hoc Tukey test. RESULTS AND CONCLUSION: Anhedonia, depression, anxiety, and craving for opiates were elevated at baseline but gradually reduced to normal within the first 1-2 months for patients who remained in treatment and did not relapse. There were no significant between-group differences prior to treatment dropout as well as between those who relapsed and who continued on naltrexone. CONCLUSION: These data do not support concerns that naltrexone treatment of opioid dependence precipitates anhedonia, depression, anxiety or craving for opiates.

[A pharmacogenetic analysis of dopaminergic and opioidergic genes in opioid addicts treated with the combination of naltrexone and guanfacine]. / Farmakogeneticheskii analiz vliyaniya genov dofaminovoi i opioidnoi sistem na effektivnost' kombinirovannoi terapii naltreksonom i guanfatsinom bol'nykh opioidnoi zavisimost'yu.

AIM: To evaluate an effect of opioid receptor and dopamine system gene polymorphisms on the efficacy of combined treatment with oral naltrexone and guanfacine in a randomized double blinded double dummy placebo controlled clinical trial. MATERIAL AND METHODS: Three hundred and one patients with opioid dependence were randomized into 4 treatment groups: naltrexone 50 mg/day + guanfacine 1 mg/day (N+G); naltrexone + placebo guanfacine (N+GP); placebo naltrexone + guanfacine (NP+G); double placebo (NP+GP). The primary outcome was treatment retention. All enrolled participants were genotyped for polymorphisms in the following genes: mu- (OPRM1), kappa-opioid receptors (OPRK1), catechol-O-methyltransferase (COMT), dopamine receptors types 2 (DRD2) and 4 (DRD4), dopamine-beta-hydroxylase, and dopamine transporter (SLC6A3, DAT1) and alpha-2-adrenoreceptor (ADRA2A) a pharmacological target of guanfacine. RESULTS: The efficacy of the combination of naltrexone and guanfacine was comparable to naltrexone monotherapy. Regardless of treatment, several gene polymorphisms were associated with higher chance to complete the treatment program: allele Т DRD4 - 521 С/Т (rs1800955) (р=0.039; OR (95% CI)=3.7 (1.1-12.7); log-rank test: р=0.01); allele С DRD2 С957Т (rs6277) (р=0.03; HR=0.6 (0.34-0.95); genotype combination: DRD4 VNTR (LL) + OPRM1 A118G (rs1799971) (AA), р=0.051; DRD2 C957T (ТТ) + OPRM1 (rs1074287) (СС), р=0.025; DRD2 - 141С (II) + OPRM1 (rs510769) (АА), р=0.035; DBH Fau(СС) + OPRM1 (rs1074287) (СС), р=0.0497. Regardless of treatment several polymorphisms were associated with high risk of relapse: allele Т (rs510769) OPRM1 (р=0.053), allele А (rs1799971, A118G) OPRM1 (р=0.056), allele S exon III 48 bp DRD4 VNTR (р=0.001; HR=3.1 (ДИ 95% 1.57-6.18); genotype combinations: DRD4 - 521 С/Т (ТТ) + DRD2 Nco I (TT), р=0.026; DRD4 -521 С/Т (ТТ) + DRD2 -141 С (II), р=0.011; DRD4 - 521 С/Т (ТТ) + OPRM1 A118G (rs1799971) (AA), р=0.011; DRD2 Nco I(ТТ) + ADRA2A (СС), р=0.012; DRD2 Nco I(ТТ) + OPRM1 A118G (AA), р=0.02. The effects dependent on the treatment group were as follows: 1) in the N+G group, patients with the DRD4 -521 С/Т TT genotype had higher probability of completion of treatment program in comparison with other genotypes (CC and CT) (log-rank test: p=0.002); 2) in NP + GP group, patients with the OPRM1 rs510769 T allele had higher risk of relapse compared to the genotype GG (p=0.008) (FDR p<0.0125). CONCLUSION: The additive effect of opioid receptor genes and dopaminergic system genes on outcomes of treatment opioid dependence with oral naltrexone and guanfacine was shown. Pharmacological effects of naltrexone and guanfacine were associated with genetic variants of the DRD4 - 521C/T polymorphism, since its effect was shown only in the N+G group. The effect of the OPRM1 rs510769 polymorphism was demonstrated in the double placebo group that was associated with personality traits (temperament, character) and determined compliance. Genetic analysis is useful for determining potential responders to treatment of opioid dependence; genotyping can increase the efficacy of pharmacotherapy.

[A double-blind randomized placebo-controlled study of the efficacy of the combined treatment with naltrexone and guanfacine for relapse prevention in opiate dependence].

OBJECTIVE: Authors studied the effect of α-2-adrenoreceptor agonist guanfacine on replace prevention in opiate addicts. MATERIAL AND METHODS: Three hundred and one recently detoxified opiate addicts were randomized under the double-blind double-dummy conditions into one of four treatment groups: naltrexone 50 mg/day+guanfacine 1 mg/day (N+G), naltrexone+guanfacine placebo (N+GP), naltrexone placebo+guanfacine (NP+G), and double placebo (NP+GP). The primary outcome was retention in treatment. The secondary outcomes were perceived stress (Perceived Stress Scale) and craving. RESULTS: At the end of six months, 20 (26.7%) patients in the N+G group and 15 (19.7%) (p=0.26 to N+G) in N+GP group were retained in treatment compared to 5 (6.7%) in the NP+G group (p=0.002 to N+G group and p=0.017 to N+GP group) and 8 (10.7%) in the double placebo group (p=0.013 to N+G group). There is no significant difference in retention between the N+G group and N+GP group at the end of treatment. CONCLUSION: Guanfacine had significant craving and stress reducing effect. Naltrexone was more effective than placebo for relapse prevention in opioid dependent patients. The efficacy of the combination of naltrexone and guanfacine was comparable to naltrexone alone. Guanfacine moderately reduced both stress and craving.

[Stabilization of remission in patients with opioid dependence with naltrexone implant: a pharmacogenetic approach]. / Stabilizatsiia remissii u bol'nykh opiinoi narkomaniei implantom naltreksona: farmakogeneticheskii aspekt.

AIM: To evaluate the effect of opioid receptor genes and dopamine system genes polymorphisms on treatment outcomes of opioid dependence with implantable and oral naltrexone. MATERIAL AND METHODS: Authors carried out a randomized double-blind, double-dummy, placebo-controlled clinical trial. Three hundred and six patients with opioid dependence were randomized into 3 equal treatment groups. The first group received implantation of 1000 mg naltrexone every 2 months during 6 months + oral naltrexone placebo; the second group - placebo implant every 2 months + oral naltrexone (50mg/day) and the third group - placebo implant + oral naltrexone placebo. It was genotyped polymorphisms in the following genes: mu-opioid receptor (OPRM1), kappa-opioid receptor (OPRK1), catechol-O-methyltransferase (COMT), dopamine receptors types 2 (DRD2) and 4 (DRD4), dopamine-beta-hydroxylase, and dopamine transporter (DAT1). RESULTS: Regardless of treatment several polymorphisms of these genes were associated with high risk of relapse: an allele L (2R) DRD4 120bp (p=0.05; OR (95% CI)=3.3(1.1-10.1)); an allele С DRD2 NcoI (р=0,051; OR (95% CI)=2,86 (1,09-7,52)); the genotype 9.9 DAT VNTR 40bp (р=0,04; OR (95% CI)=1,4 (1,3-1,5)); on the contrary, (СС+СТ)-(ТТ)) variants of OPRK1-DRD2Ncol increased a chance to complete treatment program (р=0,004; OR (95% CI)=7.4 (1.8-30.4)), Kaplan-Meier survival analysis (р=0,016). The probability of completing treatment program by the carriers of these variants was higher in the oral naltrexone group (p=0.016), lower in the double placebo group (p=0.015), but did not influence on treatment outcomes in the naltrexone-implant group. CONCLUSION: Naltrexone-implant is a highly effective medication for treatment of opioid dependence and its effectiveness exceeds that of oral naltrexone and placebo. The study has shown the joint influence of opioid receptor genes and genes of dopaminergic system on treatment outcomes of opioid dependence. Genetic analysis is useful for determining potential responders to naltrexone treatment of opioid dependence.

[Morphine-induced Straub tail reaction as a model of spasticity in mice: effects of serotonergic compounds]. / Vyzvannaia morfinom reaktsiia Shtrauba kak model' spastichnosti u myshei: éffekty serotoninergicheskikh soedinenii.

AIM: To adopt and validate the Straub tail reaction (SR) for comparative assessment of spastic effects of serotonergic compounds. MATERIAL AND METHODS: To measure the muscle relaxant activity, the morphine-induced Straub-tail assay was used. SR was graded according to modified intensity-score basis in a scale decribed by Kameyama et al. (1978). Subcutaneous injections of different doses of morphine (10-60 mg/kg) induced a dose-dependent SR with maximum response obtained 15-30 min after the morphine administration. RESULTS AND CONCLUSION: The centrally acting muscle relaxant baclofen (3-10 mg/kg) reduced SR induced by morphine (40 mg/kg) at all used doses; tizanidine decreased the intensity of SR at highest doses tested (0.6 and 1 mg/kg). Dantrolene (20-100 mg/kg), a peripherally acting muscle relaxant, did not affect SR. Effects of serotonergic agents depended on the specific mechanism of action. SR appears to be available for rapid evaluation of the effect of antispasticity drugs.

[Naltrexone implant treatment of polydrug dependence]. / Primenenie implanta naltreksona dlia terapii polinarkomanii.

Objective. Recent studies indicate that naltrexone implant may be one of the effective pharmacological treatments for opiate dependence. However, nowadays many of addicts are polydrug dependent. The aim of the study was to evaluate the effectiveness of naltrexone implant in the treatment of opiate and amphetamine polydrug dependence. Material and methods. A 10-week randomized, double-blind, placebo-controlled trial with 100 patients dependent on opiates and amphetamines has been conducted. Subjects were randomized in 1:1 ratio to either naltrexone implant or identically looking placebo formulation group. Primary outcome measures were retention in the study, proportion of drug-free urine samples and improvement in the Clinical Global Impression (CGI) scale. Results. At week 10, the retention was 52% among patients with naltrexone vs. 28% among patients with placebo implant (p=0.01), and the proportion of drug-free urine samples was 38% vs. 16% (p=0.01), respectively. Fifty-six per cent of patients treated with naltrexone implant showed marked improvement on CGI compared with 14% of patients treated with placebo (p<0.001, NNT=3.95%, CI 2-4). Conclusion. Naltrexone implant administration resulted in higher retention in the treatment, decreased heroin and amphetamine use, and improved clinical condition of patients, providing the first evidence on effective pharmacological treatment of this kind of polydrug dependence.

[Effect of Catechol-O-methyltransferase deficiency on reinforcing effects of cocaine (experimental study)].

Catechol-O-methyltransferase (COMT) remains an important regulatory element in prefrontal cortex dopamine homeostasis. The literature data suggest that individual differences in COMT activity (Val158Met polymorphism) might have indirect downstream effects on the reward system. The aim of the present study was to examine whether COMT deletion affects reinforcing effects of cocaine in mice. The study was conducted in male mice with homozygous COMT deletion as well as their C57BL/6J wild-type littermates. Animals were trained to nose-poke to receive response-contingent intravenous infusions of cocaine (0.3 mg/kg per infusion; final schedule of reinforcement - fixed ratio (FR) 3 time out 30 s). Following the initial acquisition phase, cocaine self-administration dose-effect functions (0.03, 0.1, 0.3, 1, and 3 mg/kg per infusion) were determined under FR3 and progressive ratio (PR) schedules of reinforcement. Cocaine dose-dependently maintained responding under FR3 and PR schedule of reinforcement when the unit dose of cocaine was varied across the sessions. The total cocaine intake did not differ in COMT deletion mice and wild-type mice. The results of this study suggest that individual differences in COMT activity do not affect primary reinforcing effects of cocaine in mice.

[The use of different forms of naltrexone in the treatment of opioid dependence].

The authors compared the results of own studies and foreign publications on the use of different formulations of naltrexone (peroral, implantable, injectable) for the remission stabilization and relapse prevention in patients with opioid dependence. Opioid antagonists, in particular naltrexone, are the unique medication for the specific pharmacotherapy of opioid dependence currently approved in the Russian Federation. The main problem that considerably reduces the efficacy and restricts the use of naltrexone in the treatment of opioid dependence is the problem of compliance. Nevertheless, in the double blind randomized placebo-controlled trials, we have demonstrated the higher efficacy of peroral naltrexone for the remission stabilization compared to analogous foreign publications. It might be explained by the cultural specifics of the family in the Russia Federation, in particular, by the possibility to control the treatment by relatives of the patient. However the possibilities of this control are significantly reduced as the patient gets older. Long-acting depot formulations of naltrexone (implantable and injectable) are more effective than peroral ones that allows to solve the problem of compliance and opens new perspectives in the treatment of opiate dependence.

Interaction of blockers of ionotropic NMDA receptors and metabotropic glutamate receptors in a working memory test in rats.

Glutamate, the main excitatory neurotransmitter in the mammalian CNS, acts via ionotropic and metabotropic receptors. Results from in vitro studies demonstrating tight interactions between ionotropic NMDA receptors and subtype 5 metabotropic glutamate receptors (mGlu5) have shown that blockade of mGlu5 receptors increases the behavioral effects of NMDA receptor antagonists. The aim of the present work was to study the actions of the highly selective mGlu5 receptor antagonist MTEP alone and in combination with MK-801, a blocker of the NMDA receptor-associated ion channel, on performance of a delayed selection task (a test of working memory) in rats. MK-801 (0.1 mg/kg) induced a specific impairment to working memory, with proactive interference (degradation of the ability to remember current information because of the effects of previously learned material). Administration of MTEP (5.0 mg/kg) combined with both solvent and with MK-801 had no significant effects, demonstrating the small or nonexistent involvement of mGlu5 receptors in the mechanisms of working memory.

[Naltrexone and fluoxetine for maintenance of remission in patients with heroin addiction: a double-blind randomized placebo-controlled trial].

Two hundreds and eighty patients with heroin addiction were randomized into 4 equal groups. Patients of the group 1 received naltrexone (N) in dosage 50 mg/day and fluoxetine (F) in dosage 20 mg/day during 6 months. Group 2 received N/F-placebo (FN), group 3--N-placebo (NP)/F and group 4--NP/FP. All patients underwent a session of individual psychotherapy for the maintenance of remission. Express urine drugs tests were used for remission control. Compliance was controlled by a riboflavin marker. Clinical state, psychiatric status and social functioning were assessed using quantified international scales and tests. To the end of the 6 month course, 43% of patients of group 1, 36% of group 2, 21% of group 3 and 10% of group 4 were in remission. Therefore, N/F was more effective than F/NP (p < 0.01) and FP/NP (p < 0.001); N/FP was more effective than F/NP (p < 0.05) and NP/FP (p < 0.001); F/NP did not differ significantly from NP/FP (p = 0.1); N/F did not differ from N/FP (p = 0.2). However N/F was more effective compared to N/FP only in women, probably, due to the higher baseline levels of depression, anxiety and anhedonia. Naltrexone was superior to placebo and fluoxetine in the efficacy of maintenance of remission and preventing relapse in patients with heroin addiction. The combination of naltrexone and fluoxetine was more effective compared to the monotherapy with naltrexone in women only.

[Effects of NMDA and metabotropic glutamate receptors antagonists in working memory task in rats].

Glutamate, major excitatory neurotransmitter in mammalian CNS, acts via ionotropic and metabotropic receptors. In agreement with the results of in vitro studies that pointed at close interactions between ionotropic NMDA and metabotropic glutamate mGlu5 receptors, blockade ofmGlu5 receptors was reported to enhance behavioral effects of NMDA receptor channel blockers. The present study aimed to study the effects of a highly selective mGluR5 antagonist MTEP, alone and in combination with NMDA receptor channel blocker MK-801, in rats trained to perform a delay-non-match-to-position task (working memory test). Acute administration of MK-801 (0.1 mg/kg) produced specific working memory impairment expressed as proactive interference (poor performance in the current trial due to the interfering influence of the experience in past trials). However, administration of MTEP (5.0 mg/kg), either alone or in combination with MK-801, had no appreciable effects. While these data clearly indicate little or no involvement of mGlu5 receptors in the mechanisms of working memory, present results demonstrate a robust experimental approach to study cognitive deficits associated with psychotomimetic drug treatment.

Binge drinking and unsafe sex: a study of narcology hospital patients from St. Petersburg, Russia.

The purpose of this study was to assess the association between binge alcohol use and unprotected sex in Russian substance users. Participants (N = 181) were narcology hospital patients assessed on demographics, alcohol use, risky sex, and sexually transmitted disease/human immunodeficiency virus (STD/HIV) diagnoses. Adjusted generalized estimating equations (GEEs) logistic regression analysis examined the association between binge drinking and same-day unprotected sex across each of the past 30 days, per participant (N = 5430 observations). Participants were age 18 to 55 years, 75% male, and 64% binge drinking. Sex trade was reported by 27%; history of STDs by 43%; and HIV by 15%. One fourth of daily observations included sex; 88% of these involved unprotected sex. Binge drinking was not associated with same-day unprotected sex (adjusted odds ratio [OR(adj)] = 1.0, 95% confidence interval [CI] = 0.7-1.4, chi(2)(1, N = 5219) = 0.01, ns). Findings document substantial HIV/STD risk and prevalence among Russian narcology patients, but no link between binge drinking and unprotected sex in this population, possibly due to very low rates of condom use generally.

Overcoming opioid blockade from depot naltrexone (Prodetoxon).

AIM: To describe a situation in which an opioid-dependent patient overcame naltrexone blockade. DESIGN, CASE REPORT, SETTING: Addiction treatment center in St Petersburg, Russia. PARTICIPANT: Patient with naltrexone implant. INTERVENTION: Detoxification. MEASUREMENTS: Clinical observations. CONCLUSIONS: It is possible, but very difficult, to overcome naltrexone blockade by using large doses of heroin.

Co-morbidity of infectious and addictive diseases in St. Petersburg and the Leningrad Region, Russia.

The Russian health care system is organized around specific diseases, with relatively little focus on integration across specialties to address co-morbidities. This organizational structure presents new challenges in the context of the recent epidemics of injection drug use (IDU) and HIV. This paper uses existing and new data to examine the prevalence of reported new cases of drug dependence (heroin) and HIV over time as well as associations between drug dependence and alcoholism, hepatitis B and C, and tuberculosis in the City of St. Petersburg and the Leningrad region. We found a sharp rise in reported cases of IDU beginning in 1991 and continuing until 2002/2003, followed by a sharp rise in newly reported cases of HIV. These rises were followed by a drop in new cases of HIV and drug addiction in 2002/2003 and a drop in the proportion of HIV-positive individuals with IDU as a risk factor. Infection with hepatitis B and C were common, especially among injection drug users (38 and 85%, respectively), but also in alcoholics (7 and 14%). Tuberculosis was more common in alcoholics (53%) than in persons with alcoholism and drug dependence (10%), or with drug dependence alone (4%). Though these data have many limitations, they clearly demonstrate that drug dependence and/or alcoholism, HIV, hepatitis, and tuberculosis frequently co-occur in St. Petersburg and the Leningrad Region. Prevention and treatment services across medical specialties should be integrated to address the wide range of issues that are associated with these co-morbidities.

Caffeine withdrawal syndrome in social interaction test in mice: effects of the NMDA receptor channel blockers, memantine and neramexane.

Antagonists acting at N-methyl-D-aspartate (NMDA) receptors have been demonstrated repeatedly to attenuate the expression of drug and alcohol withdrawal syndromes. The present study aimed to evaluate the effects of NMDA receptor blockade on the expression of behavioural signs of caffeine withdrawal syndrome, assessed using the social interaction paradigm. Adult male Swiss mice were treated with increasing doses of caffeine (40-100 mg/kg, i.p., twice daily) for 8 days. Twenty-four hours after the last injection of caffeine, there were significant increases in duration and frequency of defensive behaviours, as well as decreased locomotor activity. These changes faded within 72 hours. Pretreatment with a single dose of caffeine (1 mg/kg; 24 h after the end of repeated caffeine administration and 30 min prior to the test) completely reversed these withdrawal-related changes. Separate groups of mice were treated i.p. with different doses of memantine (1, 3 or 10 mg/kg) or neramexane (MRZ 2/579; 1, 3 or 10 mg/kg) 24 h after the last caffeine injection. Both compounds dose-dependently reduced the expression of defensive behaviours while increasing motor activity. These data suggest that NMDA receptor blockade may counteract the acute behavioural effects of caffeine withdrawal.

[Pharmacotherapy in heroin addiction: pharmacological approaches to remission stabilization and recurrence prevention]. / Farmakoterapiia geroinovoi narkomanii: farmakologicheskii podkhod k stabilizatsii remissii i profilaktike retsidivov.

After withdrawal arrest in many heroin addicts, they displayed the syndrome of anhedonia including affective disorders (depression, dysphoria, anxiety), dyssomnia and a pathologic craving for opiates. Anhedonia is often the cause for recurrence in heroine addiction, therefore, an appropriate treatment is an important aspect in recurrence prevention and remission stabilization. Since depression and drive for heroin are the key symptoms in anhedonia, we undertook the efficiency study of therapy (in anhedonia) by antidepressants belonging to the selective serotonin reuptake inhibitors (SSRI) and NMDA receptor antagonists, citalopram and memantine, respectively, which have a clinical antidepressant action and an experimental anti-addictive action. Both drugs were found to arrest effectively virtually all signs of anhedonia, however, their action on remission stabilization was rather moderate. It looked to be more promising to use, in remission stabilization, the uttermost antagonist of opiate receptors (naltrexone) blocking reliably all heroine effects. A double blind placebo-controlled study, undertaken by us, convincingly showed a significantly smaller number of relapses with naltrexone in heroin addicts. At the same time, the drug had no valuable effect on the anhedonia symptoms, which worsened the compliance entailing a poorer therapy efficiency. Finally, a combination of naltrexone (blocking the heroin action and reducing the recurrence rate) with SSRI antidepressants (effectively arresting the anhedonia symptoms and improving the compliance with naltrexone medication and remission quality) is a most promising approach to remission stabilization and recurrence prevention.

Opioid-NMDA receptor interactions may clarify conditioned (associative) components of opioid analgesic tolerance.

Recent evidence suggests that acute administration of opioid analgesic drugs (such as morphine or heroin) produces delayed hyperalgesia. This hyperalgesic response is likely to result from hyperactivation of NMDA receptors triggered by stimulation of opioid receptors and may mediate acute tolerance. In support of this hypothesis, blockade of NMDA receptors attenuates opioid-induced delayed hyperalgesia and prolongs the duration of antinociceptive activity of morphine. Furthermore, the NMDA receptor-induced hyperalgesia is likely an unconditioned response to opioid receptor stimulation that becomes spatiotemporally associated with environmental cues accompanying repeated opioid exposure. This hypothesis conforms to the traditional Pavlovian requirement for conditioned and unconditioned responses to be qualitatively similar. In support of the role of NMDA receptor hyperactivation in morphine tolerance, NMDA receptor antagonists have been shown to block development of analgesic tolerance induced by repeated exposures to morphine. The view of the conditioned nature of opioid tolerance may be significantly extended by assuming that upon repeated drug administration an early-onset effect of a drug may become a predictive stimulus for a later-onset effect and, consequentially, it may become empowered to elicit the later-onset effect itself. Such 'intra-drug' conditioning hypothesis is well in line with the current experimental evidence but further studies will be needed to verify it directly.

Prevention of suicide by naltrexone in a recently detoxified heroin addict.

This case describes a heroin addict who was participating in a placebo-controlled randomized trial of naltrexone as an aid to relapse prevention. The patient tried to commit suicide by taking a heroin overdose after learning that he was HIV-positive. He was on naltrexone at the time and, as a result, survived what would probably have been a fatal overdose. This case demonstrates that naltrexone can have immediate as well as long-term positive effects in persons who are attempting to recover from heroin addiction.