Ongoing Cocaine Use Research Articles

25846 Broadening the spectrum of cocaine induced neutrophilic dermatoses

A 46-year-old Caucasian female with a medical history of substance use disorder (cocaine), rheumatoid arthritis, and chronic obstructive pulmonary disease presented from an outside hospital with a two week history of painful, hemorrhagic bullae and plaques first noted on her hands and feet which then spread to her trunk over the following week. She also noted painful tongue, lip, and labial lesions as well. Given the lesional morphology in the setting of ongoing cocaine use, dermatology was consulted due to concern of levamisole-induced vasculitis.

Effects of the mGluR2/3 receptor agonist LY379268 on the reinforcing strength of cocaine in rhesus monkeys.

Because chronic cocaine exposure produces profound effects on brain glutamate function, this system has been investigated as a target for novel medications for cocaine use disorder. Studies in animal models have provided encouraging results for drugs that target metabotropic glutamate receptors (mGluR), particularly group II mGluRs which includes mGluR2 and mGluR3 receptors. The present study examined the effects of the mGluR2/3 receptor-selective agonist, (-)-2-oxa-4-aminobicylco hexane-4,6-dicarboxylic acid (LY379268), in male rhesus monkeys self-administering cocaine under two procedures that assess the strength of cocaine as a reinforcer. In four monkeys, acute effects of LY379268 on food and cocaine self-administration were characterized using a multiple 10-response fixed-ratio food, progressive-ratio cocaine schedule of reinforcement. Maximum injections were delivered when the available cocaine dose was 0.01-0.1 mg/kg.When monkeys self-administered 0.03 mg/kg per injection cocaine, LY379268 (0.001-0.56 mg/kg, i.v.), increased cocaine injections and disrupted food-maintained responding. Another group of monkeys (n = 3) responded under a food-cocaine choice procedure in which a dose-effect curve for self-administered cocaine (0.0, 0.003-0.1 mg/kg per injection) was generated daily. Acute LY379268 (0.01-0.1 mg.kg, i.v.) produced a shift in allocation of responding towards cocaine without affecting the total reinforcers delivered. When treatment was extended to 5 consecutive days, tolerance developed to LY379268-induced increases in cocaine choice. These data from two complimentary nonhuman primate models of cocaine use disorder are consistently negative with respect to the potential of LY379268 as a pharmacotherapy for reducing ongoing cocaine use.

The Effects of a Selective Serotonin 2C (5HT2C) Receptor Agonist WAY 163909 on Cocaine Self‐Administration in Male and Female Rhesus Macaques Exposed to Early Life Stress

Cocaine use disorder represents a prominent health concern in the United States, and there are currently no accepted pharmacotherapies for the treatment of ongoing cocaine use. Additionally, the occurrence of stressors early in life, such as physical abuse and neglect, is a major predictor in the emergence of cocaine abuse later in life. Rhesus monkeys demonstrate a similar prevalence rate of infant abuse and rejection as humans, and serve as ideal candidates to examine the relationship between early life stress (ELS) and cocaine use. Finally, previous data suggest serotonin 2C (5HT2C) agonists may be viable candidates in the treatment of ongoing drug use. Accordingly, the effectiveness of the 5HT‐2C agonist WAY 163909 (WAY) to decrease cocaine self‐administration was examined in male and female rhesus macaques.Subjects were 8 adolescent male and female rhesus macaques who experienced infant maltreatment (MALT) or competent maternal care (MALT males n=4; MALT females, n=2; Control males, n=0; Control females, n=2). During adolescence, animals were trained to respond under a fixed‐ratio 20 response (FR 20) schedule of reinforcement to receive an infusion of cocaine (0.01–0.1 mg/kg/infusion). After meeting criteria for stable self‐administration (SA), animals progressed through a full dose‐effect curve to establish the dose that engendered the highest response rate (EDMax), and were then examined under maintenance conditions. During each testing week, WAY pretreatments (3 consecutive daily treatments administered 45 minutes prior to sessions) were preceded by normal maintenance sessions without any pretreatments, which provided a baseline of responding. Each WAY dose (0.1–1 mg/kg IM) was tested weekly interspersed by weeks of vehicle treatment.WAY dose‐dependently decreased cocaine self‐administration in males and females, with males demonstrating significantly lower response rates in comparison to females at 0.3 mg/kg WAY. MALT animals also demonstrated an overall lower response rate across doses of WAY in comparison to control subjects.These preliminary data suggest that females may be more resistant to serotonergic interventions of ongoing cocaine SA, given that females from MALT and Control groups were less sensitive to the effects of WAY in comparison to males. Furthermore, MALT animals overall showed a lower response rate in comparison to control animals across doses of WAY, suggesting that MALT subjects may be uniquely sensitive to serotonergic interventions aimed at decreasing ongoing drug use. The addition of male controls will be critical in determining whether robust sex differences persist, and if male controls demonstrate a similar response pattern as female controls.Support or Funding InformationThis research was supported by USPHS grants DA 038588 (MMS/LLH), DA 010344 (LLH), DA 031246 (LLH), and P51OD11132 (YNPRC).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

161 - Effect of Beta-Blocker Therapy on Hospital Readmission and Mortality in Heart Failure Patients with Ongoing Cocaine Use

Background: Beta blockers are first line agents for reduction of symptoms, hospitalization and mortality in heart failure patients with reduced ejection fraction (HFrEF). However, the safety and efficacy of continuous beta-blocker therapy (BBT) in patients who actively use cocaine remain controversial and available literature is limited. We aimed to evaluate the effect of BBT on hospital readmission and mortality in HFrEF patients with ongoing cocaine use. Methods: We conducted a retrospective chart review of patients with a new diagnosis of HFrEF between 2011 and 2014 based on ICD9-CM codes. We included patients aged 18 and older who tested positive for cocaine on a urine toxicology test obtained at the time of index admission. Patients were followed for 1 year. We assessed for Beta-blocker prescription rate at the time of discharge from the index admission. A multivariate logistic regression was used to assess the effect of BBT on the 30-day all-cause and heart failure related readmissions. The 1-year mortality rate was also reported. Results: In our study population N = 268 and mean age [in yrs] = 54 (std = 6.9), the beta-blocker prescription rate is 86.2%. The 30-day readmission rate for BBT vs no BBT groups were 20% vs 41% (OR 0.17, 95% CI = 0.05–0.56, P = .004) for heart-failure related readmissions and 25% vs 46% (OR 0.19, 95% CI = 0.06–0.64, P = .007) for all-cause readmissions. The 1-year mortality rates for BBT vs no BBT groups were 5% vs 8% (OR 0.88, 95% CI = 0.17–7.19, P = .91). Conclusion: Physicians continue to prescribe outpatient Beta-blocker for most HFrEF patients regardless of cocaine-use status. BBT reduces 30-day all-cause and heart failure related readmission rate but not 1-year mortality in HFrEF patients with ongoing cocaine use. Large observational studies are needed to further elucidate the efficacy and safety of continuous BBT in this population.

Methadone maintenance therapy and viral suppression among HIV-infected opioid users: The impacts of crack and injection cocaine use

BackgroundMethadone maintenance therapy (MMT) is associated with improved HIV treatment outcomes among people who use drugs (PWUD). The extent to which these benefits are sustained in the context of ongoing cocaine use is unclear. We assessed differential impacts of MMT on HIV viral load (VL) suppression in relation to discrete patterns of cocaine use. MethodsData was drawn from ACCESS, a prospective cohort of HIV-positive PWUD in Vancouver, Canada. Generalized linear mixed-effects were used to model the independent effect of MMT on VL suppression across strata of frequency of cocaine injection and crack smoking (≥daily versus <daily), after adjustment for confounders. ResultsThe analysis included 397 HIV-positive opioid users who completed ≥1 study interview between 2005 and 2014. At baseline, 304 (77%) reported participation in MMT, 37 (9%) ≥daily cocaine injection, and 158 (40%) ≥daily crack smoking. In adjusted analyses, MMT remained independently associated with increased odds of VL suppression in both strata of crack smokers (AOR=3.11, 95% CI: 1.86–5.21 and AOR=1.48, 95%CI: 1.04–2.09, for ≥daily and <daily smokers, respectively), and among <daily cocaine injectors (AOR=1.88, 95%CI 1.38–2.56), but not among ≥daily cocaine injectors (AOR=1.37, 95%CI 0.53–3.49). Longer retention on MMT was positively associated with VL suppression in all strata of cocaine injection and crack smoke. ConclusionsExposure to MMT was associated with increased odds of VL suppression among HIV- positive opioid users regardless of crack use. However, this beneficial effect of MMT was lost among frequent cocaine injectors with shorter retention on MMT.

Long-Term Blockade of Cocaine Self-Administration and Locomotor Activation in Rats by an Adenoviral Vector-Delivered Cocaine Hydrolase.

A promising approach in treating cocaine abuse is to metabolize cocaine in the blood using a mutated butyrylcholinesterase (BChE) that functions as a cocaine hydrolase (CocH). In rats, a helper-dependent adenoviral (hdAD) vector-mediated delivery of CocH abolished ongoing cocaine use and cocaine-primed reinstatement of drug-seeking for several months. This enzyme also metabolizes ghrelin, an effect that may be beneficial in maintaining healthy weights. The effect of a single hdAD-CocH vector injection was examined in rats on measures of anxiety, body weight, cocaine self-administration, and cocaine-induced locomotor activity. To examine anxiety, periadolescent rats were tested in an elevated-plus maze. Weight gain was then examined under four rodent diets. Ten months after CocH-injection, adult rats were trained to self-administer cocaine intravenously and, subsequently, cocaine-induced locomotion was tested. Viral gene transfer produced sustained plasma levels of CocH for over 13 months of testing. CocH-treated rats did not differ from controls in measures of anxiety, and only showed a transient reduction in weight gain during the first 3 weeks postinjection. However, CocH-treated rats were insensitive to cocaine. At 10 months postinjection, none of the CocH-treated rats initiated cocaine self-administration, unlike 90% of the control rats. At 13 months postinjection, CocH-treated rats showed no cocaine-induced locomotion, whereas control rats showed a dose-dependent enhancement of locomotion. CocH vector produced a long-term blockade of the rewarding and behavioral effects of cocaine in rats, emphasizing its role as a promising therapeutic intervention in cocaine abuse.

Cocaine Intoxication and Thyroid Storm: Similarity in Presentation and Implications for Treatment.

Introduction. Cocaine, a widely used sympathomimetic drug, causes thermoregulatory and cardiac manifestations that can mimic a life-threatening thyroid storm. Case. A man presented to the emergency department requesting only cocaine detoxification. He reported symptoms over the last few years including weight loss and diarrhea, which he attributed to ongoing cocaine use. On presentation he had an elevated temperature of 39.4°C and a heart rate up to 130 beats per minute. Examination revealed the presence of an enlarged, nontender goiter with bilateral continuous bruits. He was found to have thyrotoxicosis by labs and was treated for thyroid storm and cocaine intoxication concurrently. The patient was ultimately diagnosed with Graves’ disease and treated with iodine-131 therapy. Conclusion. Cocaine use should be considered a possible trigger for thyroid storm. Recognition of thyroid storm is critical because of the necessity for targeted therapy and the significant mortality associated with the condition if left untreated.

Effects of the kappa opioid antagonist nor‐binaltorphimine on cocaine vs. food choice and extended‐access cocaine intake in rhesus monkeys (658.6)

The dynorphin/κ opioid receptor system (KOR) has been implicated as one potential neurobiological target for treating cocaine addiction. This study determined effects of the KOR antagonist nor‐binaltorphimine (nor‐BNI) on cocaine self‐administration by rhesus monkeys responding under a novel procedure that featured two daily components: (1) 2‐h choice sessions (9‐11am) when monkeys could choose between food pellets and cocaine (0‐0.1 mg/kg/inj, IV), and (2) 20‐h “extended access” sessions (noon‐8am) when only cocaine (0.1 mg/kg/inj) was available under a fixed‐ratio schedule to promote high daily cocaine intakes. After 14 days of responding under this novel procedure, nor‐BNI (3.2 mg/kg, IM) was administered, and responding was evaluated for an additional 14 days. Consistent with previous studies, cocaine maintained a dose‐dependent increase in cocaine choice, and monkeys also self‐administered cocaine throughout the extended access component. Total daily intake averaged 7.5±0.66 mg/kg cocaine. Nor‐BNI treatment had no significant effect on cocaine choice either during or after withdrawal from extended cocaine access. These results suggest the dynorphin/KOR system does not play a major role in cocaine self‐administration under these conditions. These results also do not support the utility of KOR antagonists as medications to treat ongoing cocaine use in persons dependent on cocaine.Grant Funding Source: Funded by NIH grant R01DA026946.

Beta blocker treatment of heart failure patients with ongoing cocaine use

Beta blocker treatment of heart failure patients with ongoing cocaine use

Employment-based reinforcement of adherence to an FDA approved extended release formulation of naltrexone in opioid-dependent adults: A randomized controlled trial

Background Naltrexone provides excellent opioid blockade, but its clinical utility is limited because opioid-dependent patients typically refuse it. An injectable suspension of naltrexone for extended release (XR-NTX) was recently approved by the FDA for treatment of opioid dependence. XR-NTX treatment may require concurrent behavioral intervention to maximize adherence and effectiveness, thus we sought to evaluate employment-based reinforcement as a method of improving adherence to XR-NTX in opiate dependent adults. Methods Opioid-dependent adults ( n = 38) were detoxified and inducted onto oral naltrexone, then randomly assigned to contingency or prescription conditions. Participants received up to six doses of XR-NTX at four-week intervals. All participants could earn vouchers for attendance and performance at a therapeutic workplace. Contingency participants were required to accept XR-NTX injections to access the workplace and earn vouchers. Prescription participants could earn vouchers independent of their acceptance of XR-NTX injections. Results Contingency participants accepted significantly more naltrexone injections than prescription participants (87% versus 52%, p = .002), and were more likely to accept all injections (74% versus 26%, p = .004). Participants in the two conditions provided similar percentages of samples negative for opiates (72% versus 65%) and for cocaine (58% versus 54%). Opiate positivity was significantly more likely when samples were also cocaine positive, independent of naltrexone blockade ( p = .002). Conclusions Long-term adherence to XR-NTX in unemployed opiate dependent adults is low under usual care conditions. Employment-based reinforcement can maintain adherence to XR-NTX. Ongoing cocaine use appears to interfere with the clinical effectiveness of XR-NTX on opiate use.

Clinicopathologic Features of Agranulocytosis in the Setting of Levamisole-Tainted Cocaine

Levamisole is a known contaminant of cocaine and, via this route, has been associated with otherwise unexplained agranulocytosis. Levamisole is currently present in the majority of cocaine samples seized by the US Drug Enforcement Agency. We identified 20 cases of unexplained agranulocytosis in our practice locations of Albuquerque, NM, and Vancouver, Canada. Epidemiologic investigation revealed recent or ongoing cocaine use in 14 cases (70%). Certain morphologic features, including circulating plasmacytoid lymphocytes, increased bone marrow plasma cells, and mild megakaryocytic hyperplasia, were associated with the cocaine-exposed group. Of 5 patients tested, 3 (60%) were HLA-B27+ and showed antineutrophil antibodies, consistent with known associations of levamisole-induced agranulocytosis. One patient, who was positive for cocaine and levamisole by toxicology testing, died of infectious complications. Inadvertent consumption of levamisole via cocaine is a severely under-appreciated risk factor for agranulocytosis, and specific laboratory features are suggestive of this etiology.

The Impact of Benzodiazepine Use on Methadone Maintenance Treatment Outcomes

ABSTRACT The purposes of this study were to examine predictors of benzodiazepine use among methadone maintenance treatment patients, to determine whether baseline benzodiazepine use influenced ongoing use during methadone maintenance treatment, and to assess the effect of ongoing benzodiazepine use on treatment outcomes (i.e., opioid and cocaine use and treatment retention). A retrospective chart review of 172 methadone maintenance treatment patients (mean age = 34.6 years; standard deviation = 8.5 years; 64% male) from January 1997 to December 1999 was conducted. At baseline, 29% were “non-users” (past year) of benzodiazepine, 36% were “occasional users,” and 35% were “regular/problem users.” Regular/problem users were more likely to have started opioid use with prescription opioids, experienced more overdoses, and reported psychiatric comorbidity. Being female, more years of opioid use, and a history of psychiatric treatment were significant predictors of baseline benzodiazepine use. Ongoing benzodiazepine users were more likely to have opioid-positive and cocaine-positive urine screens during methadone maintenance treatment. Only ongoing cocaine use was negatively related to retention. Benzodiazepine use by methadone maintenance treatment patients is associated with a more complex clinical picture and may negatively influence treatment outcomes.

A comparison of 1-year substance abuse treatment outcomes in community syringe exchange participants versus other referrals

This longitudinal cohort study of 324 consecutive admissions to methadone maintenance treatment between 08/1994 and 09/1997 compared 1-year outcomes of opioid-dependent patients referred from a syringe exchange program (SEP; n = 81) versus other sources ( n = 243). All participants received stepped-based counseling. The Addiction Severity Index was completed upon admission. Treatment outcomes were assessed using weekly urine testing and days in treatment. GEE regression models were used to evaluate the association between baseline variables and treatment outcomes. SEP referrals were older, included more males and African Americans, reported greater unemployment and heavier heroin, cocaine, and injection drug use at admission. During treatment, SEP referrals used more opioids (OR 2.57; 95% CI 1.86–3.56) and cocaine (OR 2.77; 95% CI 1.93–3.95), and were less likely to complete 1 year (35%) compared to other referrals (56%; hazard ratio 1.88; 95% CI 1.35–2.62). Nevertheless, referral source was not significantly associated with outcome when adjusted for baseline characteristics. Greater baseline frequency of substance and injection drug use, and younger age were positively associated with ongoing opioid and cocaine use. African American race and baseline unemployment were also associated with ongoing cocaine use. Younger age and greater baseline cocaine use were associated with poorer retention at 1 year. The poorer treatment response of SEP referrals is likely due to higher baseline problem severity. Specialized interventions may be required to reduce drug use and improve retention in this population.

Apathy predicts hedonic but not craving response to cocaine

Cocaine-induced craving has been implicated in the maintenance of ongoing cocaine use and is presumed to be mediated by enhanced synaptic availability of monoamines, including dopamine. Apathy is a neuropsychiatric syndrome that is associated with hypodopaminergic functioning and is neurobiologically distinct from depression. Apathy has been observed to be prevalent during the initial phases of abstinence in cocaine-dependent individuals. In the current report, we sought to investigate the relationship between apathy, depression, and craving in response to an acute intravenous administration of cocaine. To this end, sixteen non-treatment seeking volunteers were evaluated. Following acute administration of cocaine (40 mg, IV), patients with low apathy scores exhibited increased craving, whereas patients with high apathy scores exhibited decreased craving. In addition, patients with high apathy scores exhibited increased ratings of the subjective measure of “High”, suggesting that high apathy predicts a greater hedonic response in dependence. Self-reported ratings of depression did not account for the observed differences. The data reveal that cocaine-induced craving is not ubiquitous, and may not play a critical role in the maintenance of cocaine dependence. Overall, the findings suggest that apathy predicts hedonic but not craving response to cocaine.

Posttraumatic stress disorder and short-term outcome in early methadone treatment.

The aim of this study was to determine treatment adherence relative to frequency of violence and posttraumatic stress disorders (PTSD) among new methadone patients. Ninety-six opiate-abusing patients were evaluated for childhood physical and sexual abuse (CPSA), adulthood exposures to violence (ADVIOL), PTSD, and treatment adherence. Overall, 43% of the subjects dropped out of treatment within 3 months of intake. Occurrence of trauma or PTSD did not predict drop-out rates. A 2 (Gender) x 2 (PTSD) analysis of covariance (ANCOVA) with severity of other drug use on admission as a covariate, however, revealed a main effect for PTSD, F(4, 71) = 7. 69, p < or =.01, such that those patients with current PTSD revealed significantly more ongoing drug use at 3 months (M = 24.3, SD = 20. 9) than those without (M = 8.9, SD = 11.8). Examination of ongoing cocaine use using a 2 (Gender) x 2 (PTSD) ANCOVA also revealed a main effect for PTSD, F(4, 17) = 8.24, p < or = .005, such that those patients with current PTSD revealed significantly more ongoing cocaine use at 3 months postadmission (M = 51.6, SD = 37.6) than those without (M = 24.3, SD = 20.9). For both genders, CPSA and ADVIOL were associated with higher rates of PTSD, which in turn predicted poorer treatment adherence as measured by ongoing co-occurring drug abuse 3 months postadmission. Results underscore the need for routine assessment and targeted treatment of trauma in methadone patients.

A Cocaine High-Risk Situations Questionnaire: development and psychometric properties.

Although high-risk situations have been identified for alcoholism, opiate abuse, and smoking, further research is needed to identify high-risk situations for cocaine abuse. A 233-item Cocaine High-Risk Situations Survey was developed based on a comprehensive literature review and was administered to 179 cocaine users in treatment. Situations that occurred infrequently or that were not often associated with cocaine use were eliminated and the remaining 89 items were factor analyzed using half the sample with confirmatory factor analysis on the remainder of the sample. Only one factor was found for frequency of cocaine use in these situations. The 21 items with high factor loadings and a diverse range of content were retained for subsequent analyses and renamed the Cocaine High-Risk Situations Questionnaire (CHRSQ). Reliability and convergent and discriminant validity of this scale were demonstrated. Frequency of alcohol use in the same situations was not significantly related to cocaine use and abuse, supporting discriminant validity. The findings suggest that the frequency of ongoing cocaine use is not determined by specific situations. Theoretical and clinical implications are discussed.

Cocaine causing convulsions in a large municipal hospital population

We reviewed all cases with a diagnosis of convulsions admitted to a large municipal hospital in 1 year and determined which of these patients had an additional diagnosis of ongoing cocaine use. Of 795 patients with convulsions, 29 also had a diagnosis of active cocaine use (4%). On review of these cases, only 4 (0.5%) were determined by history to possibly show a causal relationship between cocaine use and convulsions. On review of 22 cases of convulsions related to cocaine use over the past 4 years, 9 were found to have multiple convulsive episodes related to cocaine. Our findings suggest that cocaine is an infrequent cause of seizures in a city hospital population. However, there is a small number of patients in whom cocaine is apparently highly proconvulsant.