Cocaine-dependent Persons Research Articles

Repeated Administration of Opra Kappa (LY2456302), a Novel, Short-Acting, Selective KOP-r Antagonist, in Persons with and without Cocaine Dependence

The κ-opioid receptor (KOP-r) system and its endogenous ligands, the dynorphins, are involved in the neurobiological regulation of addictive states, and of mood. There are limited data on the impact of selective KOP-r antagonism in humans on basic biobehavioral functions, or on addictive diseases and mood disorders. Previously studied selective KOP-r antagonists have unusual pharmacodynamic and pharmacokinetic properties (slow development of KOP-r selectivity, extremely long duration of action) that limit translation to human studies. A recently developed selective KOP-r-antagonist, Opra Kappa (LY2456302; CERC-501), has medication-like duration of action, oral bioavailability, and target engagement. The current study is the first investigation of the effects of a KOP-r-antagonist in cocaine-dependent persons in comparison with normal volunteers. In a stress-minimized inpatient setting, we determined the neuroendocrine and neurobehavioral effects of repeated administration of an active dose of Opra Kappa (10 mg p.o. daily, four consecutive days in comparison with an initial baseline day). Healthy volunteers (n=40), persons diagnosed with cocaine dependence in early abstinence (<2 months, EACD) (n=23), and drug-free former cocaine-dependent persons (7-month to 25-year abstinence, DFFCD) (n=7) were studied, with measurements including circulating neuroendocrine hormones, affect, and, in cocaine-dependent persons, cocaine craving. Modest adverse events related to Opra Kappa included pruritus, observed in a subset of individuals. No significant change was observed in serum prolactin levels following Opra Kappa administration, but modest increases in circulating adrenocorticotropic hormone and cortisol were observed. No significant changes were noted in measures of depression or cocaine craving in this stress-minimized setting. Overall, these studies demonstrate that effects of 10 mg Opra Kappa are largely consistent with those predicted for a selective KOP-r antagonist. This medication regimen was tolerable, and is therefore feasible for further studies in cocaine-dependent persons.

Sleep Perception and Misperception in Chronic Cocaine Users During Abstinence.

During abstinence, chronic cocaine users experience an objective worsening of sleep that is perceived as qualitatively improving. This phenomenon has been termed "occult insomnia." The objective of this study was to determine whether chronic cocaine users experience positive sleep state misperception during abstinence. Forty-three cocaine-dependent persons were admitted to an inpatient research facility for 12 days and 11 nights to participate in a treatment study of modafinil. Polysomnographic sleep recordings were performed on study nights 3, 4, 10, and 11, when participants were on average 1 and 2 weeks abstinent from cocaine. Participants also completed sleep diary questionnaires every evening before bed and every morning upon awakening. Polysomnographic and sleep diary measurements of total sleep time, sleep latency, time awake after sleep onset, and time in bed after final awakening were compared. Chronic cocaine users accurately reported total sleep time after 1 week of abstinence but overreported total sleep time by an average of 40 min after 2 weeks of abstinence. Underestimating sleep latency and time spent awake after sleep onset were responsible for this difference. Positive sleep state misperception is revealed in chronic cocaine users after 2 weeks of abstinence and is consistent with the previously identified "occult insomnia" in this population.

Optimal neurocognitive, personality and behavioral measures for assessing impulsivity in cocaine dependence

Background: Impulsivity may underlie the poor treatment retention and high relapse rates observed in cocaine-dependent persons. However, observed differences in measures of impulsivity between cocaine-dependent and healthy control participants often do not reach clinical significance, suggesting that the clinical relevance of these differences may be limited. Objectives: To examine which measures of impulsivity (i.e. self-report impulsivity, self-report personality, neurocognitive testing) best distinguish cocaine-dependent and healthy control participants (i.e. showing differences at least 1.5 standard deviations [SD] from controls). Optimal measures were considered to demonstrate sufficient classification accuracy. Methods: Sixty-five recently abstinent cocaine-dependent and 25 healthy control participants were assessed using select neurocognitive tests and self-report questionnaires including the NEO Personality Inventory-Revised (NEO-PI-R), Temperament and Character Inventory (TCI), Barratt Impulsiveness Scale (BIS-11a), and the Frontal Systems Behavior Scale (FrSBe). Results: When corrected for years of education and gender, neurocognitive measures did not demonstrate clinically significant differences between cocaine-dependent and control participants. The personality measures TCI Purposefulness and Congruent Second Nature and NEO-PI-R Impulsiveness, and the self-rating measures FrSBe Disinhibition and BIS-11 Motor Impulsivity and Total successfully identified clinically meaningful elevations in impulsivity within cocaine-dependent participants (>1.5 SDs from controls). Furthermore, these measures achieved 84–93% accuracy in discriminating cocaine-dependent from control participants. Conclusion: Clinically significant neurocognitive impairment in cocaine-dependent participants was not observed in this sample. As the BIS-11 or FrSBe are brief to administer, accurate, and have been shown to predict treatment retention and relapse, these measures appear to be optimal, relative to the personality measures, for examining trait impulsivity in cocaine dependence.

Pilot Study of Lorazepam and Tiagabine Effects on Sleep, Motor Learning, and Impulsivity in Cocaine Abstinence

Objectives: To test the effects of mechanistically different GABA modulating agents on the disrupted sleep and cognitive function associated with abstinence from cocaine. Methods: We examined the effects of lorazepam and tiagabine on polysomnographically measured sleep and cognition in six cocaine dependent persons. Participants were studied during the first and second week of controlled abstinence following intravenous, laboratory cocaine administration. Results: Lorazepam and tiagabine decreased sleep latency, but whereas lorazepam markedly increased light sleep, tiagabine caused a dramatic shift toward slow-wave sleep. Despite increasing total sleep time, lorazepam impaired sleep dependent learning and increased next day impulsivity. Conclusions: These results introduce the possibility of different, sleep-related cognitive effects of mechanistically distinct GABAergic sedative hypnotics.

Error-processing deficits in patients with cocaine dependence

Cocaine abuse and addiction can be characterized by a persisting use of cocaine in the face of adverse consequences. In the present study we focus on one specific element of adverse consequences: the making of errors. The aim of this study was to determine whether cocaine-dependent persons have error-processing deficits as measured using error-related negativity (ERN) and error positivity (Pe). Event-related potentials (ERPs) during an Eriksen flanker task were recorded from cocaine-dependent patients and a control group. Cocaine-addicted patients showed reduced ERN and Pe components as compared to a control group. On the behavioral level, patients showed reduced post-error accuracy improvement. The present findings reveal that cocaine addiction is associated with reduced error processing and impaired behavioral correction of errors after an error is made. These deficits may be associated with a compromised dopamine system. It is argued that these cognitive deficits may contribute to the maintenance of the cocaine addiction.

Frontal lobe GABA levels in cocaine dependence: a two-dimensional, J-resolved magnetic resonance spectroscopy study

Non-invasive measures of brain gamma-aminobutyric acid (GABA) concentrations may be especially useful in the identification of cocaine-related changes in brain chemistry that can be used to guide the development of future treatments for cocaine-dependent persons. This study assessed whether brain GABA levels in cocaine-dependent subjects with and without an alcohol disorder differ from GABA levels in healthy comparison subjects. Two-dimensional, proton magnetic resonance spectroscopy was used to determine GABA levels in the left prefrontal lobe of cocaine-dependent subjects ( N=35) recruited from a National Institute on Drug Abuse (NIDA)-sponsored treatment trial of cocaine dependence and a comparison group ( N=20). At treatment baseline, mean GABA concentrations were 0.93±0.27 mM/kg in cocaine-dependent subjects and 1.32±0.44 mM/kg in the comparison sample ( t [d.f.=53]=3.65, P<0.001). Cocaine-dependent subjects with a history of a co-morbid alcohol disorder ( N=23) had significantly lower baseline GABA levels (0.87 mM/kg) ( t [d.f.=41]=4.31, P<0.001) than the comparison group. However, cocaine-dependent subjects without an alcohol disorder ( N=12) also had lower GABA levels (1.04 mM/kg) than the comparison subjects ( t [d.f.=30]=2.09, P=0.045), suggesting that cocaine dependence alone can decrease GABA levels.

Burden of medical illness in drug- and alcohol-dependent persons without primary care.

Little is known about the frequency, severity, and risk factors for disease in drug- and alcohol-dependent persons without primary medical care. Our aims are to assess the burden of medical illness, identify patient and substance dependence characteristics associated with worse physical health, and compare measures of illness burden in this population. This was accomplished through a cross-sectional study among alcohol-, heroin- or cocaine-dependent persons without primary medical care who were admitted to an urban inpatient detoxification unit. The mean age of these patients was 35.7 (SD 7.8) years; 76% were male and 46% were Black. Forty-five percent reported being diagnosed with a chronic illness, and 80% had prior medical hospitalizations. The mean age-adjusted SF-36 Physical Component Summary (PCS) score was lower than the general U.S. population norm (44.1 vs 50.1; p<0.001). In multivariable analysis, female gender (adjusted mean change in PCS score: -3.71 points, p=.002), problem use of hallucinogens (-3.51, p=0.013), heroin (-2.94, p=0.008), other opiates (-3.20, p=.045), living alone (-3.15, p=.023), having medical insurance (-2.26, p=0.014) and older age (-.22 points per year, p=0.001) were associated with worse health. From these data, it seems that alcohol- and drug-dependent persons without primary medical care have a substantial burden of medical illness compared to age- and gender-matched U.S. population controls. While the optimal measure of medical illness burden in this population is unclear, a variety of health measures document this medical illness burden in addicted persons.

Patient Treatment Choice and Compliance:Data from a Substance Abuse Treatment Program

The authors tested the hypothesis that patients (treatment-seeking cocaine-dependent persons) given the opportunity to choose between treatment approaches would do better than patients randomly assigned to the same approaches in treatment retention and 9-month outcome. Subjects were 34 patients who voluntarily chose to enter individual therapy 1 hour per week (IND) and 33 who chose intensive group therapy for 3 hours, 3 times weekly (INT). There were no significant differences between these two groups on demographic, personality, or addiction severity variables or in treatment retention or 9-month outcome. Comparison with samples of 30 patients who had been randomly assigned to IND and 30 to INT did not confirm the hypothesis that patients who chose their treatment would either remain in treatment for longer periods of time or manifest improved 9-month outcomes. The authors raise several motivational issues.

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.

Nicotine and caffeine use in cocaine-dependent individuals

Nicotine and caffeine use in 87 cocaine-dependent persons seeking treatment at an outpatient clinic were compared to use of those substances in a matched general population sample (n = 78). The prevalence of cigarette smoking was significantly greater in the cocaine-dependent sample (75% vs. 22%). Within the cocaine-dependent sample, smokers were younger, less educated, employed in lesser skilled jobs, and reported an earlier onset and more frequent use of cocaine. The prevalence of caffeine use was significantly less in the cocaine-dependent group (68% vs. 83%), although, among caffeine users, the cocaine group drank significantly more caffeinated beverages per day than matched controls (4.9 vs. 3.3). Interestingly, regular caffeine use was associated with less frequent cocaine use within the cocaine-dependent sample. To our knowledge, this study is the first to report on prevalence of smoking and caffeine use among cocaine-dependent individuals, and suggests that use of these other substances may influence the onset and pattern of cocaine use.

Treating Crack Cocaine Dependence: The Critical Role of Relapse Prevention

In order to adequately address the treatment needs of crack cocaine dependent persons, a multidimensional approach to relapse prevention must be utilized. The value of a biopsychosocial model of crack addiction and the concept of phases of recovery in providing a rationale for the recommended approach to relapse prevention are emphasized. Research findings on the determinants of relapse for crack dependent patients and the psychosocial characteristics of the crack dependent individual justify the utility of certain relapse prevention strategies. Specifically, an approach to relapse is advocated that includes the provision of pharmacological adjuncts, psychoeducation on the multideterminants of relapse, and psychotherapy that attempts to remediate underlying psychological problems that are typically found in crack dependent patients.