Early outcomes following low dose naltrexone enhancement of opioid detoxification.

Although withdrawal severity and treatment completion are the initial focus of opioid detoxification, post-detoxification outcome better defines effective interventions. Very low dose naltrexone (VLNTX) in addition to methadone taper was recently associated with attenuated withdrawal intensity during detoxification. We describe the results of a seven-day follow-up evaluation of 96 subjects who completed inpatient detoxification consisting of the addition of VLNTX (0.125 or 0.250 mg per day) or placebo to methadone taper in a double blind, randomized investigation. Individuals receiving VLNTX during detoxification reported reduced withdrawal and drug use during the first 24 hours after discharge. VLNTX addition was also associated with higher rates of negative drug tests for opioids and cannabis and increased engagement in outpatient treatment after one week. Further studies are needed to test the utility of this approach in easing the transition from detoxification to various follow-up treatment modalities designed to address opioid dependence.

Very low dose naltrexone addition in opioid detoxification: a randomized, controlled trial.

Although current treatments for opioid detoxification are not always effective, medical detoxification remains a required step before long-term interventions. The use of opioid antagonist medications to improve detoxification has produced inconsistent results. Very low dose naltrexone (VLNTX) was recently found to reduce opioid tolerance and dependence in animal and clinical studies. We decided to evaluate safety and efficacy of VLNTX adjunct to methadone in reducing withdrawal during detoxification. In a multi-center, double-blind, randomized study at community treatment programs, where most detoxifications are performed, 174 opioid-dependent subjects received NTX 0.125 mg, 0.250 mg or placebo daily for 6 days, together with methadone in tapering doses. VLNTX-treated individuals reported attenuated withdrawal symptoms [F = 7.24 (2,170); P = 0.001] and reduced craving [F = 3.73 (2,107); P = 0.03]. Treatment effects were more pronounced at discharge and were not accompanied by a significantly higher retention rate. There were no group differences in use of adjuvant medications and no treatment-related adverse events. Further studies should explore the use of VLNTX, combined with full and partial opioid agonist medications, in detoxification and long-term treatment of opioid dependence.

A retrospective case control study of alcohol relapse and spiritual growth.

In the context of an NIAAA/Fetzer Institute-funded study designed to look at the impact of spirituality in an inpatient alcohol treatment, this retrospective case control study investigated whether spiritual growth occurred during an inpatient phase of treatment for alcohol dependence, the degree to which spiritual gains (if noted) would be maintained at follow-up, and whether spiritual growth would be associated with follow-up sobriety. To accomplish this goal, thirty-six individuals who reported relapsing to alcohol at three-month follow-up were compared with thirty-six matched controls who reported abstinence at follow-up. Spiritual development and change was assessed via a set of six measures. Paired t-tests revealed that spiritual growth occurred across all measures during the treatment phase. Repeated measures analysis of variance (ANOVA) indicated that this growth was maintained at three-month follow-up. Two-way repeated measures ANOVA revealed that while non-relapsers maintained spiritual growth over the course of four weeks of treatment and in the three-month period following treatment, renewed alcohol use was associated with decreased spirituality.

Antagonist treatment of opioid withdrawal translational low dose approach.

Although antagonist drugs are receiving increasing attention in the treatment of opioid withdrawal, the mechanisms of interaction of opiate agonists and antagonists remain largely to be investigated. We focused on the effects of very low quantities of opiate antagonists, following the clinical indication of their potential utility in detoxification. Upon reviewing the evidence on the administration of small doses of naloxone and naltrexone in the presence of agonist drugs, the effects of low-dose naltrexone during opiate administration and withdrawal are described. The application of a translational methodology allowed completing the clinical design with behavioral and cellular information obtained from a specifically developed animal model. The initial results indicate that low doses of naltrexone may help reducing the manifestation of opioid withdrawal, offer suggestions for further investigations and confirm the utility of a translational research approach to the clinical neurobiology of drug addiction.

Levels of spirituality and treatment outcome: a preliminary examination.

OBJECTIVE: The primary aim of this study was to examine whether admission differences in levels of spirituality predisposed alcohol-dependent individuals to favorable or unfavorable outcomes following admission to facilities that differed in the degree to which spirituality was emphasized. It was hypothesized that individuals whose admission level of spirituality was congruent with the treatment program's orientation and who as such were considered optimally placed (i.e., "matched") for treatment would evince better in-treatment outcomes. METHOD: Four hundred and five participants completed measures of spirituality and psychosocial well-being at intake and at end of treatment. RESULTS: In examining the entire sample, no matching effects were observed on discharge status, abstinence efficacy, or desire to drink. When analyses were restricted to those cases scoring in the upper or lower quartiles in spirituality, we observed a paradoxical effect, as individuals recording lower levels of spirituality at the less spiritual program evinced significantly poorer outcomes (i.e., less abstinence efficacy, greater desire to drink). CONCLUSIONS: These findings hint at the importance of spirituality in the environment of care, indicating that individuals low in spirituality were at risk for poorer outcomes, but exposure to a program that emphasized spirituality lowered that risk.

Chronic very low dose naltrexone administration attenuates opioid withdrawal expression.

BACKGROUND: Different regimens of agonist and antagonist drugs have been used in opioid withdrawal management, with variable results. We examined whether administering extremely small quantities of opiate antagonists in the presence of opiate agonist drugs reduces withdrawal expression. METHODS: Forty-one male Sprague-Dawley rats were implanted with morphine or placebo pellets for eight days. Starting on day 3, some rats received naltrexone in their drinking water (5 mg/L), or unadulterated water. On day 8, rats were injected with saline or naltrexone (100 mg/kg) and evaluated for behavioral signs of withdrawal. Next, sections through the locus coeruleus (LC) and nucleus of the solitary tract (NTS), brainstem areas exhibiting cellular activation following opiate withdrawal, were processed for c-Fos to detect early gene expression. Finally, the same nuclei were examined for protein kinase A regulatory subunit II (PKA) and phosphorylated cyclic adenosine monophosphate response element binding protein (pCREB), using Western blot analysis. RESULTS: Withdrawal was attenuated and c-Fos, PKA, and pCREB expression was decreased in the NTS and LC of rats receiving chronic very low doses of naltrexone. CONCLUSIONS: Reduction of withdrawal upon chronic very low naltrexone administration may be due in part to decreased activation of brainstem noradrenergic neurons in morphine dependent rats.

Gender differences in cue exposure reactivity and 9-month outcome.

Gender differences have been shown to be related to the course of cocaine dependence and treatment. While previous research has shown cue exposure procedures to be somewhat effective at reducing reactivity of substance dependent individuals to drug related stimuli, the few studies that have examined gender differences in craving and cue-reactivity have yielded equivocal results. We have recently demonstrated that an active cue-exposure procedure that featured cocaine-dependent individuals receiving immediate feedback about their level of physiological arousal following videotaped exposure to cocaine-related stimuli was capable of positively influencing in-treatment (helplessness, abstinence efficacy) as well as 9-month followup outcome (i.e., urinalysis) indices (Sterling, R., Gottheil, E., Murphy, J., & Weinstein, S. (2001). Cue exposure and abstinence efficacy. College on Problems of Drug Dependence, Phoenix, AZ, June 17, 2001). The purpose of the present study was to determine whether differential in-treatment or 9-month followup outcomes were obtained for male and female study participants. Subjects in this study were 81 individuals (47 male/34 female) who met DSM-IV criteria for cocaine dependence and who had consented to be randomly assigned to either the active cue-exposure or control conditions. Participants were compared along a myriad of pre-treatment, in-treatment, and 9-month followup measures. Other than males reporting more recent employment, there was no obvious systematic pattern of differences on pre-treatment indices. No gender differences in treatment retention were observed. With respect to 9-month followup, no gender differences on measures of addiction severity, psychological functioning, or urinalyses were noted. However males were more "cue-reactive" and more successful at establishing control over their reactivity to the cocaine stimuli. Additional research is needed to determine whether these differences in reactivity can be more clearly defined and utilized positively in a treatment setting.

Pre-treatment measures of impulsivity, aggression and sensation seeking are associated with treatment outcome for African-American cocaine-dependent patients.

We investigated whether measures of impulsivity, aggression and sensation seeking differed between cocaine-dependent subjects and controls, and whether these measures were related to treatment-outcome for cocaine patients. Pre-treatment assessments of impulsivity (Barratt Impulsivity Scale [BIS]), aggression (Buss-Durkee Hostility Inventory [BDHI]) and sensation seeking (Zuckerman Sensation Seeking Scale [SSS]) were obtained for 141 African-American cocaine-dependent patients entering a 12-week, intensive outpatient treatment program and 60 controls. The outcome measures were number of negative urine drug screens, days in treatment, dropout rates and number of treatment sessions. Cocaine patients reported significantly higher scores on the SSS, the BIS and the BDHI than controls. Furthermore, the SSS scores showed a significantly negative correlation with days in treatment and negative urines, and a significant positive correlation with the dropout rate. The BIS and the BDHI scores were significantly associated with days in treatment and dropout rates respectively. A combination of the three variables contributed significantly toward predicting retention and abstinence. Higher levels of pretreatment impulsivity and aggression and sensation seeking seem to associated with poor treatment outcome for cocaine dependent patients receiving intensive outpatient treatment. Combining these behavioral measures with other clinical predictors may help in early identification of 'poor responders' who may benefit from additional or alternative treatment approaches.

Comparison of pretreatment characteristics and treatment outcomes for alcohol-, cocaine-, and multisubstance-dependent patients.

We investigated whether pretreatment characteristics and measures of outcome differed for alcohol-, cocaine-, and multisubstance-dependent patients receiving outpatient substance abuse treatment. One hundred and forty substance dependent individuals (32 alcohol, 76 cocaine, and 32 multisubstance) enrolled in a 12-week outpatient treatment program were compared across measures of addiction severity, personality, and treatment-readiness at admission. In-treatment, end-of-treatment and 9-month follow-up assessments of treatment outcome were then compared across the three groups. Outcome measures included reduction in problem severity, abstinence, retention, number of sessions attended, dropout, and counselor and patient ratings of treatment benefit. At admission, the multisubstance group had a higher proportion of positive urines, reported more severe drug, alcohol and psychiatric problems, and displayed higher impulsivity and anxiety scores than one or both of the other groups. However, multisubstance patients were more treatment ready in terms of adopting a total abstinence orientation than alcohol or cocaine patients. While a significant reduction in symptoms occurred for the total sample during treatment as well as at follow-up, comparisons of outcomes did not consistently favor any particular group. The three groups had equivalent improvements in eleven of fourteen during-treatment and five of seven follow-up measures. Despite pretreatment differences, in severity and treatment-readiness, outcomes were more similar than different for alcohol-, cocaine-, and multisubstance-dependent patients. Clinicians should be cautious about forecasting treatment-outcomes for addicted patients based on their primary substances of abuse.

Relationship between platelet serotonin uptake sites and measures of impulsivity, aggression, and craving among African-American cocaine abusers.

We investigated whether platelet-tritiated paroxetine binding, a measure of serotonin uptake sites, and behavioral measures of impulsivity, aggression, and craving differed between cocaine-dependent subjects and controls and whether paroxetine binding was related to these behavioral measures. One hundred and five African-American cocaine-dependent outpatients and 44 African-American controls were studied. Tritiated paroxetine binding sites on platelets were assayed, and standardized assessments of impulsivity, aggression, and craving were performed. The Bmax values of paroxetine binding were significantly reduced among cocaine patients compared to controls. Cocaine patients showed significantly higher scores on certain measures of sensation seeking, impulsivity, and aggression as compared to controls. Furthermore, paroxetine binding showed a significant negative correlation with most measures of sensation seeking, impulsivity, and aggression--though not craving--among cocaine patients. Our findings indicate that densities of serotonin uptake sites may be reduced among cocaine abusers and related to impulsive-aggressive behavioral dimensions.

A genetic association study of the mu opioid receptor and severe opioid dependence.

OBJECTIVES: Twin, family and adoption studies have suggested that vulnerability to opioid dependence may be a partially inherited trait (Cadoret et al., 1986; Merikangas et al., 1998; Tsuang et al., 1998, 2001). Studies using animal models also support a role for genetic factors in opioid dependence, and point to a locus of major effect on mouse chromosome 10 (Berrettini et al., 1994; Alexander et al., 1996), which harbors the mu opioid receptor gene (Mor1) (Kozak et al., 1994). The gene encoding the human mu opioid receptor (OPRM1) is thus an obvious candidate gene for contributing to opioid dependence. A recent report (Hoehe et al., 2000) found a significant association between a specific combination of OPRM1 single nucleotide polymorphisms (SNPs) and substance dependence. METHODS: In the current study, we genotyped 213 subjects with severe opioid dependence (89 African-Americans, 124 European-Americans) and 196 carefully screened "supercontrol" subjects (96 African-Americans, 100 European-Americans) at five SNPs residing in the OPRM1 gene. The polymorphisms include three in the promoter region (T-1793A, -1699T insertion and A-1320G) and two in exon 1 (C+17T [Ala6Val] and A+118G [Asp40Asn]). RESULTS: Statistical analysis of the allele frequency differences between opioid-dependent and control subjects for each of the polymorphisms studied yielded P values in the range of 0.444-1.000. Haplotype analysis failed to identify any specific combination of SNPs associated with the phenotype. CONCLUSIONS: Despite reasonable statistical power we found no evidence of association between the five mu opioid receptor polymorphisms studied and severe opioid dependence in our sample. There were, however, significant allele frequency differences between African-Americans and European-Americans for all five polymorphisms, irrespective of drug-dependent status. Linkage disequilibrium analysis of the African-American genotypes indicated linkage disequilibrium (P<0.0001) across the five-polymorphism, 1911 base pair region. In addition, only four haplotypes of these five polymorphisms are predicted to exist in African-Americans.

High- and low-structure treatments for substance dependence: role of learned helplessness.

We studied whether pretreatment levels of learned helplessness (LH) were related to outcomes for substance-dependent individuals receiving high-structure, behaviorally oriented (HSB) or low-structure, facilitative (LSF) treatment. The subjects were 120 substance-dependent patients randomly assigned to the HSB or the LSF treatment style for up to 12 weeks of weekly individual counseling. The two groups were compared across pretreatment characteristics as well as in-treatment, end-of- treatment, and 9-month postadmission follow-up outcome measures. Outcomes reflected reduction in problem severity, abstinence, retention, dropout rate, and ratings of treatment benefit. Significant and comparable reductions in symptoms occurred for the HSB and LSF patients both during treatment and at follow-up. Comparisons of other outcomes also did not consistently favor either treatment style. However, significant and consistent interactions were observed between LH and treatment styles with respect to several outcome measures, and these effects were independent of pretreatment levels of depression, addiction severity, and readiness for treatment. Specifically, the more "helpless" patients did significantly better in HSB treatment, whereas the less "helpless" patients had better outcomes in LSF treatment. A matching approach that assigns patients to high- and low-structure treatments based on pretreatment levels of LH might improve treatment outcomes for substance-dependent patients.

Use of very low-dose naltrexone during opiate detoxification.

The use of antagonist drugs to reduce the duration of opiate detoxification severely enhances withdrawal symptoms. To investigate the feasibility of administering antagonists with opiates without intense withdrawal during detoxification, 5 methadone maintained patients were evaluated while tapering methadone and receiving at the same time very low (0.125 mg), then increasing daily doses of naltrexone in the course of a 6-day, day hospital treatment. Reduced quantities of adjunctive medications were administered, as compared to the standard protocols, the treatment was completed without incidents or particular discomfort and all patients were easily induced to naltrexone maintenance by the day of discharge. Controlled studies will clarify whether very low-dose naltrexone provides a safe and comfortable detoxification technique to reduce withdrawal intensity and duration without the problems of heavy sedation, as suggested by the description of these clinical cases.

Coping styles and response to high versus low-structure individual counseling for substance abuse.

We compared outcomes during and after treatment for mixed substance dependent patients (N=143) randomly assigned to a high-structure, behaviorally-oriented (HSB) or a low-structure, facilitative (LSF) individual counseling style. We hypothesized that patients with different coping characteristics would respond differently to the two styles of counseling. Patients were treated in once-weekly individual HSB or LSF counseling for up to 12 weeks. Outcome measures included patient and counselor ratings of benefit, retention, symptom reduction, and negative urines; follow-up assessments included control of substance use and psychosocial adjustment. While no differences in outcomes during or after treatment were found for the HSB and LSF patients, both groups did improve equally. Contrary to our hypothesis, our coping measures did not predict different outcomes for patients treated in the LSF and HSB styles. Post-hoc analyses, however, revealed that outcomes could be predicted in each style from patterns of pretreatment characteristics, which included measures of coping strategies, psychological characteristics, and treatment readiness. Moreover, the patterns associated with positive outcomes were different for the HSB and LSF patients: high treatment readiness was most important for success in HSB counseling, while low psychiatric severity and positive coping styles were important for the LSF clients. The finding of no HSB-LSF outcome differences calls into question the exclusive emphasis on behavioral treatment approaches by the present-day managed care industry. Also, the traditional approach to matching studies, ie, employing one patient characteristic at a time to predict differential outcomes for particular treatments, may be simplistic. An alternative approach employing multivariate statistical procedures to predict outcomes from several patient characteristics may hold more promise.

Relationship between platelet serotonin uptake sites and treatment outcome among African-American cocaine dependent individuals.

We investigated whether platelet tritiated paroxetine binding, a measure of serotonin uptake sites differed between cocaine-dependent subjects and controls, and whether paroxetine binding was related to treatment-outcome for cocaine patients. One hundred twenty-five African-American cocaine-dependent individuals receiving outpatient treatment and 44 controls were studied. Tritiated paroxetine binding sites on platelets were assayed and standardized assessments of behavior were performed. The outcome measures were number of negative urine drug screens, days in treatment, dropout rates and number of treatment sessions attended. Cocaine patients had significantly lower Bmax values of paroxetine binding compared to controls. Furthermore, Bmax values showed a significant positive correlation with days in treatment and negative urines. A combination of Bmax and Addiction Severity Index (ASI) employment scores improved the prediction of days in treatment and a combination of Bmax and ASI drug scores enhanced the prediction of negative urines. The findings indicate that serotonergic mechanisms may be involved in cocaine dependence and may influence treatment-outcome among cocaine patients.

Self-administration of both ethanol and nicotine in rats.

Self-administration of either nicotine (NIC) or ethanol (ETH) has been extensively studied. This study addressed for the first time the self-administration of both substances when offered together. Male and female rats of different ages were offered NIC and ETH using the two- or three-bottle free-choice method. When NIC and ETH were offered together at different concentrations to young male rats (about 45 days old), intake of NIC increased with increasing NIC concentrations, and intake of ETH increased with decreasing ETH concentrations, but these effects were independent of the presence of the second drug. These rats also consumed the same amounts of NIC or ETH regardless of whether offered individually or together. A prior choice of only NIC or ETH did not affect a subsequent intake of both drugs offered together. A choice of both drugs for 24 h for several days followed by a choice for only 2 h for several days showed the same intake of NIC but a decreased intake of ETH for the shorter period. Young female rats (about 45 days old) and older male rats (about 75 days old) consumed the same amounts of NIC but less ETH than did the young male rats. These results show that young male rats voluntarily consume NIC and ETH independently of each other and that preexposure to one drug does not affect the subsequent intake of both drugs in combination. The data also suggest that these drugs act on different reward centers which have to be 'satisfied' independently of each other.

Tobacco and alcohol use and medical symptoms among cocaine dependent patients.

Despite the widespread use of tobacco and alcohol by illicit drug users, the medical effects of smoking and alcohol use remain understudied among such individuals. We investigated the relationship between smoking and alcohol use, and medical symptoms among 125 cocaine dependent patients. Subjects were assessed for smoking, alcohol use, and medical problems using a standardized self-report instrument (MILCOM). Medical symptoms were compared among nonsmokers, moderate smokers (less than 10 cigarettes per day), and heavy smokers (10 or more cigarettes per day) using partial chi-square statistics. Similar comparisons of medical symptoms were made between alcohol users (more than 2 drinks per day) and nonusers. Contrary to our expectations, there were no significant differences between nonsmokers, moderate smokers, and heavy smokers across most of the 14 major medical systems. However, regardless of the level of cocaine use, nonsmokers reported the fewest symptoms on the general subscale (p < 0.05) while moderate smokers reported the most nose/throat and respiratory symptoms (p < 0.01) among the three groups. As expected, significant relationships were observed between medical symptoms and alcohol use. Alcohol users reported more respiratory (p < 0.05), cardiovascular (p < 0.01), digestive (p < 0.05), head/neck (p < 0.001), eye (p < 0.01), and general (p < 0.05) symptoms than nonusers. While the findings generally support the link between alcohol and medical problems, it seems that the relationship between medical symptoms and smoking among cocaine patients may be more complex than that observed in the general population.

No association between polymorphisms in the serotonin transporter gene and susceptibility to cocaine dependence among African-American individuals.

Genetic research of cocaine abuse has been relatively limited among the African-American population. Since the serotonin transporter (5HTT) may be involved in modulating effects of cocaine, we investigated whether allelic variants of the 5HTT gene may confer susceptibility to cocaine dependence among African-American individuals. One hundred and fifty-six cocaine-dependent subjects and 82 controls were studied. Polymerase chain reaction-based genotyping of a variable-number-tandem-repeat (VNTR) marker yielded three alleles designated 12, 10 and 9. Genotype and allele frequencies were compared using chi-square analyses. We found no differences between subjects and controls with respect to genotype distribution (cocaine: 12/12 = 50%, 10/12 = 35.3%, 10/10 = 13.5%, 9/12 = 1.3%; controls: 12/12 = 42.7%, 10/12 = 39.0%, 10/10 = 17.1%, 9/12 = 1.2%). Similarly, allele frequencies of the VNTR marker did not differ between the two groups (cocaine: 12 = 68.3%, 10 = 31.1%, 9 = 0.6%; controls: 12 = 62.8%, 10 = 36.6%, 9 = 0.6%). Our findings do not seem to support a relationship between VNTR polymorphisms and cocaine dependence among African-American patients. Further studies involving larger samples are required to confirm our results.

Predicting treatment-outcome in cocaine dependence from admission urine drug screen and peripheral serotonergic measures.

We investigated whether urine drug screens (UDS) at admission and platelet paroxetine binding, a measure of serotonin transporter sites, were related to outcome measures for cocaine patients in treatment. Tritiated paroxetine binding sites on platelets were assayed and UDS were obtained for 105 African American cocaine-dependent outpatients. Outcome measures included number of negative urines, days in treatment, dropouts, and number of treatment sessions attended. A significant association was found between cocaine-positive UDS at admission and negative urines, treatment retention, dropouts, and treatment sessions; while Bmax values of paroxetine binding (density of serotonin transporter sites) were significantly associated with treatment retention and negative urines. Moreover, UDS and paroxetine binding combined to enhance prediction of retention and abstinence. Although both admission UDS and paroxetine binding seem to contribute individually in predicting outcome of cocaine patients, a combination of the two variables seems to have a stronger effect in terms of predicting treatment-outcome.