Predictors of Treatment Outcome in Outpatient Cocaine and Alcohol Dependence Treatment

We examined the ability of several baseline variables to predict treatment outcome in a pharmacotherapy trial that included 164 participants who were both cocaine‐ and alcohol‐dependent and were selected for a randomized, double‐blind, placebo‐controlled study. Predictor variables included results from the baseline Addiction Severity Index (ASI), initial Urine Drug Screen results, cocaine and alcohol craving and cocaine and alcohol withdrawal symptoms at the start of treatment. Successful treatment was defined as four continuous weeks of self‐reported cocaine abstinence verified by urine drug screens. In respect to demographic characteristics, there were no significant differences between patients who achieved four weeks of abstinence from cocaine and those who did not. Baseline variables that most consistently predicted cocaine abstinence included initial urine drug screen (UDS) results, the initial Cocaine Selective Severity Assessment (CSSA) scores, and initial self‐reported cocaine use in past 30 days, whereas cocaine craving, cocaine composite scores, alcohol craving, alcohol withdrawal symptoms, and alcohol composite scores did not. The results of this study suggest that cocaine dependence severity in general, and initial UDS results, the CSSA scores and frequency of recent cocaine use in particular, have a significant impact on treatment outcome in the treatment of cocaine‐dependent patients with comorbid alcoholism. Initial UDS results and CSSA scores are very useful predictors of treatment outcome and could be used as stratifying variables in outpatient cocaine and alcohol medication trials.     

Gender differences in individuals with comorbid alcohol dependence and post-traumatic stress disorder

This study investigated gender differences in a sample of outpatient, treatment-seeking individuals (N=84) with comorbid alcohol dependence and post-traumatic stress disorder (PTSD). Assessments included substance use severity, trauma history, PTSD symptomatology, and comorbid psychiatric disorders. Men reported an earlier age of onset of alcohol dependence, greater alcohol use intensity and craving, and more severe legal problems due to alcohol use. Women reported greater exposure to sexually related traumas, greater frequency and intensity of avoidance of trauma-related thoughts and feelings, and greater social impairment due to PTSD. Women were more likely than men to demonstrate higher rates of other anxiety disorders and test positive for cocaine at treatment entry. PTSD more often preceded alcohol dependence in women than in men. The results illustrate a number of gender differences that may shed light on etiologic models of comorbid alcohol dependence and PTSD.     

Outcome predictors in cocaine dependence treatment trials

Finding the predictors of outcome in outpatient cocaine dependence treatment trials may be useful for the development of both psychosocial as well as pharmacological treatments for cocaine dependence. Among the most powerful predictors of response to psychosocial treatment are cocaine withdrawal symptom severity and the results of a urine drug screen (UDS) collected at study entry. The present trial seeks to extend these findings by examining outcome predictors in a large number of subjects participating in a series of outpatient cocaine pharmacotherapy trials while selecting three separate criteria to define successful outcome. The ability of several baseline variables were tested to predict treatment outcome in a series of cocaine medication trials that included 402 cocaine-dependent subjects. Predictor variables included results from the baseline Addiction Severity Index (ASI), initial UDS results, and cocaine withdrawal symptom severity at treatment entry, as measured by scores on the Cocaine Selective Severity Assessment (CSSA). Outcome measures included UDS results obtained during the trials and results from the ASI gathered at the end of the trials. Baseline variables that most consistently predicted treatment outcome were the initial UDS results and initial CSSA scores. These findings indicate that baseline UDS results and CSSA scores are powerful predictors of outcome and should be used as stratifying variables in outpatient cocaine medication trials.     

Cocaine withdrawal symptoms identify "Type B" cocaine-dependent patients

Recent studies of substance dependence typologies briefly show that multivariate systems originally developed for identifying subtypes of alcoholics, such as Babor's Type A and B system, may also be valid in abusers of other substances, such as cocaine. Type B patients are characterized by an earlier onset of addiction and more severe symptoms of their addiction, psychopathology, and impulsivity. The Type B classification has also been associated with deficits in serotonergic function. We have found that patients who exhibit more severe cocaine withdrawal symptoms, as measured by scores on the Cocaine Selective Severity Assessment (CSSA), have poor treatment outcome and share many characteristics with "Type B" patients. In this paper, we review baseline characteristics of cocaine-dependent patients from several recently completed outpatient cocaine dependence treatment trials to assess the association of cocaine withdrawal symptom severity and the Type B profile. Identifying subtypes of cocaine-dependent patients may improve our ability to treat cocaine dependence by targeting treatments for specific subtypes of patients. We examined the ability of the CSSA scores to capture Type B characteristics in cocaine dependence by analyzing a series of cocaine medication trials that included 255 cocaine-dependent subjects. High CSSA scores at baseline were associated with a history of violent behavior, a family history of substance abuse, antisocial personality disorder, higher addiction severity, and co-morbid psychiatric diseases. Patients with high CSSA scores are also more likely to meet criteria for Type B (Type II) cocaine dependence. Identifying Type B cocaine-dependent patients may help to develop targeted psychosocial or pharmacological treatments for these difficult-to-treat patients.     

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.     

Bromocriptine for Cocaine Dependence

On the basis of the dopamine depletion theory, bromocriptine has been tested to treat cocaine withdrawal and dependence. The authors conducted a 6-week study with 1 week of pretreatment observation and 5 weeks of a randomized, double-blind, placebo-controlled clinical trial of bromocriptine for DSM-III-R-defined cocaine dependence in methadone-maintained male patients. The bromocriptine group (n = 24) did not differ from the placebo group (n = 26) in self-reported cocaine use, proportion of positive urine toxicology samples, craving for cocaine, resistance to cocaine use, or mood symptoms between the pretreatment baseline and the last week of the clinical trial. Both groups showed significant reduction in self-reported frequency of cocaine use, resistance to craving, and mood symptoms during participation in the protocol. The results of this study are consistent with recent clinical and laboratory findings in primary cocaine users. Despite initially promising pilot studies, recent evidence does not support the efficacy of bromocriptine to reduce cocaine use or craving.     

Coherence of the dependence syndrome in cocaine users

The method of diagnosing drug dependence introduced in DSM-III-R is largely untested for drugs other than alcohol. Cocaine, unlike alcohol, lacks clearly identifiable withdrawal symptoms, yet is also considered highly addictive. Can criteria derived from the dependence syndrome concept be generally applied to treatment seeking cocaine users? To evaluate the coherence of the dependence syndrome elements for cocaine, factor analysis models are applied to the nine dichotomous DSM-III-R drug-dependence criteria derived from structured clinical interviews with 399 cocaine users. A single factor model, in which both the centrality and severity of each criteria were assessed, adequately describes the criteria and supports the coherence of the dependence syndrome concept for cocaine. Pre-occupation was the most central criterion in defining cocaine dependence. However, avoiding withdrawal through the use of other drugs measured the most severe level of drug dependence. Inability to stop using the tolerance were only minimally related to the measurement of cocaine dependence.     

A Double-Blind Amino Acids,L-Tryptophan and L-Tyrosine,and Placebo Study with Cocaine-Dependent Subjects in an Inpatient Chemical Dependency Treatment Center

In a six-month double-blind study in an inpatient chemical dependency facility, 29 cocaine-dependent subjects were studied to determine if the amino acids, L-tryptophan and L-tyrosine, would decrease cocaine craving and withdrawal symptoms. Those subjects receiving placebo were shown to have a statistically significant increase in only one physical symptom category. The drug craving and other major physical and subjective symptoms were not shown to be significant. This study is consistent with a literature review in demonstrating that the amino acids do not significantly reduce most symptoms of cocaine craving and withdrawal when used alone.     

A double-blind amino acids, L-tryptophan and L-tyrosine, and placebo study with cocaine-dependent subjects in an inpatient chemical dependency treatment center

In a six-month double-blind study in an inpatient chemical dependency facility, 29 cocaine-dependent subjects were studied to determine if the amino acids, L-tryptophan and L-tyrosine, would decrease cocaine craving and withdrawal symptoms. Those subjects receiving placebo were shown to have a statistically significant increase in only one physical symptom category. The drug craving and other major physical and subjective symptoms were not shown to be significant. This study is consistent with a literature review in demonstrating that the amino acids do not significantly reduce most symptoms of cocaine craving and withdrawal when used alone.     

Prolactin serum levels during alcohol withdrawal are associated with the severity of alcohol dependence and withdrawal symptoms

Background: Prolactin serum levels have been described to be elevated during alcohol withdrawal in alcohol‐dependent patients and normalize during abstinence. Alterations in prolactin levels may reflect disturbances of dopaminergic neurotransmission which is of crucial importance for alcohol‐seeking behavior. Methods: In this longitudinal observational study, we investigated prolactin serum levels in 99 male patients during the first 14 days of alcohol withdrawal and early abstinence and in 43 healthy controls. To assess the severity of alcohol dependence, the extent of withdrawal symptoms, craving, depressive symptoms, and anxiety, we employed a structured interview including psychologic measurements. Results: Prolactin serum levels were elevated during the whole study period in alcohol‐dependent patients compared to the healthy control group. Prolactin levels at admission (first day of alcohol withdrawal) were associated with the severity of alcohol withdrawal (CIWA‐Ar) and of alcohol dependence (SESA) but not with the other assessed psychologic parameters. Conclusions: The presented findings confirm that prolactin is significantly elevated in alcohol‐dependent patients during alcohol withdrawal and early abstinence, not showing a rapid decline after cessation of drinking. The association with the severity of withdrawal and dependence may reflect at least partially the individual alterations in the dopaminergic and glutamatergic pathways.     

A Review of Pharmacotherapies for Substance Abuse

New pharmacotherapies have been developed for acute withdrawal and maintenance treatments of alcohol and opioid dependence but not for cocaine dependence. High-dose, long-acting benzodiazepines, beta-blockers, and two antiseizure agents—carbamazepine and valproate—are being used for alcohol withdrawal. For maintenance treatment, opioid antagonists and various serotonergic agents, such as fluoxetine and ondansetron, show promise. For opioid dependence, clonidine-naltrexone detoxification appears quite cost-effective, and buprenorpbine and LAAM (levo-alpha-acetylmethadol) show promise for both detoxification and maintenance. More work is needed, however, to discover an effective agent for target populations of cocaine abusers.     

Neuropeptide Y receptor genes are associated with alcohol dependence, alcohol withdrawal phenotypes, and cocaine dependence

Background: Several lines of evidence in both human and animal studies suggest that variation in neuropeptide Y (NPY) or its receptor genes (NPY1R, NPY2R and NPY5R) is associated with alcohol dependence as well as alcohol withdrawal symptoms. Additional studies suggest that cocaine may affect NPY expression. Methods: A total of 39 single nucleotide polymorphisms (SNPs) were genotyped across NPY and its 3 receptor genes in a sample of 1,923 subjects from 219 multiplex alcoholic families of European American descent recruited as part of the Collaborative Studies on the Genetics of Alcoholism (COGA) study. Family‐based association analysis was performed to test the primary hypothesis that variation in these genes is associated with alcohol dependence. Secondary analyses evaluated whether there was an association of these SNPs with symptoms of alcohol withdrawal, cocaine dependence, or comorbid alcohol and cocaine dependence. Results: Although variations in NPY itself were not associated with these phenotypes, variations in 2 NPY‐receptor genes were. SNPs in NPY2R provided significant evidence of association with alcohol dependence, alcohol withdrawal symptoms, comorbid alcohol and cocaine dependence, and cocaine dependence (all p < 0.03). Haplotype analyses strengthened the evidence for these phenotypes (global 0.0004 < p < 0.005). SNPs in NPY5R demonstrated significant association with alcohol withdrawal characterized by seizures (p < 0.05). Conclusion: These results indicate that sequence variations in NPY receptor genes are associated with alcohol dependence, particularly a severe subtype of alcohol dependence characterized by withdrawal symptoms, comorbid alcohol and cocaine dependence, and cocaine dependence.     

Nicotine dependence is associated with compulsive alcohol craving

Aims To investigate a possible association of nicotine dependence and alcohol craving. Design A prospective cross‐sectional study on patients diagnosed with alcohol dependence. Setting Detoxification unit of a regional psychiatric hospital. Participants A total of 127 smoking male patients were included in the study at admission for detoxification from alcohol. Measurements The Fagerström Test for Nicotine Dependence (FTND) was used to assess the severity of nicotine dependence while the Obsessive Compulsive Craving Scale (OCDS) was used to measure alcohol craving. The OCDS was assessed at admission and after 7 days of withdrawal treatment, distinguishing the total score, the obsessive and the compulsive subscale. Findings Spearman’s correlation revealed a significant association between the extent of alcohol craving and the FTND score (day 0, n = 127: OCDS total score r = 0.238, P = 0.007; OCDS compulsive score r = 0.280, P = 0.001; day 7; n = 94: OCDS total score r = 0.212, P = 0.040; OCDS compulsive score r = 0.225, P = 0.029). Conclusions The severity of nicotine dependence is associated with higher craving in alcohol‐dependent patients. These results point towards shared pathophysiological mechanisms in alcohol craving and nicotine addiction.     

The Use of Diphenoxylate Hydrochloride (Lomotil) in the Management of the Minor Withdrawal Syndrome during Methadone Detoxification: A Clinical Report

Diphenoxylate Hydrochloride (Lomotil) was effective in alleviating the minor withdrawal symptoms that accompanies complete methadone detoxification. None of the subjects developed a tolerance to Lomotil nor did they experience withdrawal symptoms or craving when Lomotil was discontinued. This report indicates that the elimination of this minor withdrawal syndrome facilitates complete methadone detoxification.     

Temporal progression of cocaine dependence symptoms in the US National Comorbidity Survey

Objective Cocaine dependence first appeared as a diagnostic category in 1987 with the publication of DSM‐III‐R. While the temporal sequencing of alcohol symptoms has a long history, little such attention has been focused on cocaine dependence. This paper examines the retrospective recall of DSM‐III‐R cocaine dependence symptom progression among a large sample of cocaine users and the relationship of these symptoms to psychiatric comorbidity. Methods Using data from the US National Comorbidity Survey, DSM‐III‐R criterion ‘A’ cocaine dependence symptoms were sequenced temporally based on age of symptom onset. Each of these numerical symptom strings was examined to determine its prevalence and association to comorbid psychiatric disorders. Results Cocaine users represented 16% of the sample. Although hundreds of symptom sequence permutations are possible, only a few are highly prevalent. Subjects whose early onset symptoms are neuroadaptive (e.g. tolerance and withdrawal) are more likely to develop cocaine dependence than subjects whose early symptoms are characterized by psychosocial consequences. Furthermore, certain temporal patterns were found to increase or decrease the presence or absence of cocaine dependence and psychiatric comorbidity. Finally, psychiatric comorbidity preceded rather than followed cocaine use onset disproportionately. Conclusions Like alcohol users, cocaine users follow a limited array of symptom sequence pathways from first use to dependence. By better understanding and examining the temporal progression of drug use symptoms, clinicians might improve screening and assessment activities and determine more effectively the extent of risks associated with continued premorbid drug use and enhance treatment‐matching. We encourage clinicians to develop evaluation instruments that specifically ask patients to sequence their cocaine use‐related symptoms temporally.     

Gender differences in cocaine craving among non-treatment-seeking individuals with cocaine dependence.

The purpose of this pilot study was to evaluate potential gender differences in cocaine craving among non-treatment seekers with cocaine dependence. We examined 10 female and 11 male individuals matched by demographic characteristics and severity of drug use; we used a multidimensional questionnaire that assesses various aspects of craving: (a) current intensity, (b) projected intensity, (c) resistance to use cocaine, (d) responsiveness to drug-related conditioned stimuli, and (e) imagined likelihood of use if in a setting with access to drugs. Other instruments utilized were the Hamilton Rating Scale for Depression and Addiction Severity Index. Female subjects had higher total craving scores (p < .05), with post hoc tests showing more present desire to use cocaine and responsivity to drug-conditioned stimuli, along with lower scores on the desire not to use cocaine. In exploratory analyses, we found greater depressive symptomatology (p = .02) and severity of family/social problems (p = .02) in females than their males counterparts. These results suggest that gender may influence different aspects of cocaine craving. As estrogen is purported to modulate craving-related dopaminergic systems, further studies will be needed to confirm these observed gender differences and to investigate their possible mechanisms, particularly estrogen-dopamine interactions and their effect on craving and mood.     

Disulfiram treatment for cocaine dependence in methadone-maintained opioid addicts

Aims: Cocaine use by patients on methadone maintenance treatment is a widespread problem and is associated with a poorer prognosis. Recent studies have evaluated disulfiram as a treatment for individuals with comorbid alcohol and cocaine abuse. We evaluated the efficacy of disulfiram for cocaine dependence, both with and without co-morbid alcohol abuse, in a group of methadone-maintained opioid addicts. Design: Randomized double-blind, placebo-controlled trial. Setting: Urban methadone maintenance clinic. Participants: Sixty-seven cocaine-dependent, methadone-maintained, opioid-dependent subjects (52% female; 51% Caucasian). Intervention: Study medication, either disulfiram or placebo, was placed directly in the methadone to ensure compliance for 12 weeks. Measurements: Primary outcome measures included weekly assessments of the frequency and quantity of drug and alcohol use, weekly urine toxicology screens and breathalyzer readings. Findings: Disulfiram treated subjects decreased the quantity and frequency of cocaine use significantly more than those treated with placebo. Alcohol use was minimal for all subjects regardless of the medication. Conclusions: Disulfiram may be an effective pharmacotherapy for cocaine abuse among methadone-maintained opioid addicts, even in those individuals without co-morbid alcohol abuse. Disulfiram inhibits dopamine beta-hydroxylase resulting in an excess of dopamine and decreased synthesis of norepinephrine. Since cocaine is a potent catecholamine re-uptake inhibitor, disulfiram may blunt cocaine craving or alter the "high", resulting in a decreased desire to use cocaine.     

A Placebo-Controlled Elimination Study to Identify Potential Treatment Agents for Cocaine Detoxification

This open-label study was done to determine which of several recommended agents and rationales may be effective for outpatient detoxification of cocaine dependence. A total of 324 cocaine-dependent persons were sequentially assigned to subgroups of 8–23 subjects and detoxified with 20 different treatment agents. Subjects who received each treatment agent were compared to a control group of 18 subjects who received only placebo and amino acids. Fourteen of the 20 agents (70%) appeared inappropriate for outpatient cocaine detoxification because they demonstrated intolerable side effects, a first-week drop-out rate over 40%, or failed to reduce urine cocaine metabolite concentrations. Cocaine use appeared to increase with bromocriptine mesylate, levodopa, and phenmetrazine hydrochloride, since mean cocaine urine concentration increased during treatment. Although no agent was statistically superior in performance to the placebo (control) group on any evaluation criterion, amantadine hydrochloride, bupropion hydrochloride, mazindol, nifedipine, pentoxifylline, and prazosin hydrochloride did not demonstrate any obvious liabilities and warrant further study as outpatient cocaine detoxification agents.     

Citicoline in addictive disorders: a review of the literature

Background: Citicoline is a dietary supplement that has been used as a neuroprotective agent for neurological disorders such as stroke and dementia. Citicoline influences acetylcholine, dopamine, and glutamate neurotransmitter systems; serves as an intermediate in phospholipid metabolism; and enhances the integrity of neuronal membranes. Interest has grown in citicoline as a treatment for addiction since it may have beneficial effects on craving, withdrawal symptoms, and cognitive functioning, as well as the ability to attenuate the neurotoxic effects of drugs of abuse. Objectives: To review the literature on citicoline’s use in addictive disorders. Methods: Using PubMed we conducted a narrative review of the clinical literature on citicoline related to addictive disorders from the years 1900–2013 using the following keywords: citicoline, CDP-choline, addiction, cocaine, alcohol, substance abuse, and substance dependence. Out of approximately 900 first hits, nine clinical studies have been included in this review. Results: Most addiction research investigated citicoline for cocaine use. The findings suggest that it is safe and well tolerated. Furthermore, citicoline appears to decrease craving and is associated with a reduction in cocaine use, at least at high doses in patients with both bipolar disorder and cocaine dependence. Limited data suggest citicoline may also hold promise for alcohol and cannabis dependence and in reducing food consumption. Conclusions: Currently, there is limited research on the efficacy of citicoline for addictive disorders, but the available literature suggests promising results. Future research should employ larger sample sizes, increased dosing, and more complex study designs.     

Withdrawal symptoms do not predict relapse among subjects treated for cannabis dependence

This is the first follow-up study on the association between cannabis withdrawal symptoms and risk of relapse to cannabis use. Withdrawal symptoms were assessed in 36 subjects seeking treatment for cannabis dependence. All were free of other substance use or alcohol abuse in the month before abstinence from cannabis. Follow-up was performed 26+/-4 months later, and at this point, the withdrawal symptoms were re-assessed. The following symptoms were significantly elevated after abstinence compared with follow-up: irritability, anger, depression, restlessness, craving, sleep problems, strange dreams, increased appetite, violent outbursts, sweating, hot flashes, chills, and shakiness. This offers further validation of a cannabis withdrawal syndrome. Average withdrawal scores at baseline did not differ with gender, age, treatment type, extent of cannabis use, or a lifetime history of anxiety or affective disorders. Withdrawal scores at baseline did not predict relapse during follow-up.