Gerardo Gonzalez

Desipramine and contingency management for cocaine and opiate dependence in buprenorphine maintained patients

Co-dependence on opiates and cocaine occurs in about 60% of patients entering methadone treatment and has a poor prognosis. However, we recently found that desipramine (DMI) could be combined with buprenorphine to significantly reduce combined opiate and cocaine use among these dually dependent patients. Furthermore, contingency management (CM) has been quite potent in reducing cocaine abuse during methadone maintenance. To test the efficacy of combining CM with these medications we designed a 12-week, randomized, double blind, four cell trial evaluating DMI (150 mg/day) or placebo plus CM or a non-contingent voucher control in 160 cocaine abusers maintained on buprenorphine (median 16 mg daily). Cocaine-free and combined opiate and cocaine-free urines increased more rapidly over time in those treated with either DMI or CM, and those receiving both interventions had more drug-free urines (50%) than the other three treatment groups (25-29%). Self reported opiate and cocaine use and depressive and opioid withdrawal symptoms showed no differences among the groups and symptom levels did not correlate with urine toxicology results. Lower DMI plasma levels (average 125 ng/ml) were associated with greater cocaine-free urines. DMI and CM had independent and additive effects in facilitating cocaine-free urines in buprenorphine maintained patients. The antidepressant appeared to enhance responsiveness to CM reinforcement.

Combating opiate dependence: a comparison among the available pharmacological options.

Pharmacotherapies for heroin addiction may target opiate withdrawal symptoms, facilitate initiation of abstinence and/or reduce relapse to heroin use either by maintenance on an agonist or antagonist agent. Available agents include opioid agonists, partial opioid agonists, opioid antagonists and α2-agonists for use during managed withdrawal and long-term maintenance. Experimental approaches combine α2-agonists with naltrexone to reduce the time of opiate withdrawal and to accelerate the transition to abstinence. Recently, buprenorphine has been introduced in the US for office-based maintenance, with the hope of replicating the success of this treatment in Europe and Australia. Naloxone has been added to buprenorphine in order to reduce its potential diversion to intravenous use, whilst facilitating the expansion of treatment. Although comprehensive substance abuse treatment is not limited to pharmacotherapy, this review will focus on the rationale, indications and limitations of the range of existing medications for detoxification and relapse prevention treatments. The two major goals of pharmacotherapy are to relieve the severity of opiate withdrawal symptoms during the managed withdrawal of the opioid and to prevent relapse to heroin use either after abstinence initiation or after being stabilised on a long-acting opiate agonist, such as methadone.

Prediction of Treatment Outcome by Baseline Urine Cocaine Results and Self‐Reported Cocaine Use for Cocaine and Opioid Dependence

This study examined the usefulness of baseline cocaine urine toxicology results and self‐reported days of cocaine use in predicting treatment response in cocaine‐ and opioid‐dependent subjects. Ninety‐nine male and 52 female subjects, maintained on buprenorphine, participated in a 24‐week, randomized, double‐blind, four‐cell trial that evaluated desipramine (150 mg/d) or placebo plus contingency management or a noncontingent voucher control. Out of 151, 102 (67%) subjects had cocaine‐positive and 49 (32%) cocaine‐negative urines at the beginning of treatment. For the previous 30 days before study participation, 91 (60%) subjects reported using cocaine 15 or less days (low baseline cocaine use) and 60 (40%) subjects reported more than 15 days (high baseline cocaine use). By using the treatment effectiveness score (TES) as the outcome measure, a negative urine for cocaine at baseline predicted a better outcome during a 24‐week trial for cocaine and opioid use. There also was a significant interaction between baseline cocaine urine results and desipramine response with the urine cocaine‐negative group showing greater desipramine response than placebo for opioid and cocaine use. Self‐reported cocaine use at baseline did not show significant predictive power for TES scores during the clinical trial. These results suggest that baseline cocaine urine results should be considered as stratifying variables in clinical trials for cocaine dependence.

Comorbid major depressive disorder as a prognostic factor in cocaine-abusing buprenorphine-maintained patients treated with desipramine and contingency management

Depression is common among patients who abuse both opiates and cocaine, and its treatment has had mixed success. This study compares buprenorphine‐maintained patients with lifetime major depressive disorder (MDD, N = 53) with those never depressed (ND, N = 96) on cocaine and opiate‐free urines during a 12‐week outpatient double‐blind, placebo‐controlled, randomized clinical trial. The 149 subjects were assigned to four groups: 1) desipramine (DMI) + contingency management (CM); 2) DMI + noncontingency management (NCM); 3) placebo + CM; and 4) placebo + NCM. Depression assessments included Hamilton Depression Rating Scale, Center for Epidemiological Studies Depression Inventory, and Structured Clinical Interview for DSM‐IV interview for diagnosis of lifetime MDD. Urine toxicologies were performed thrice weekly and the CES‐D was performed monthly. The MDD group had a larger proportion of females (45% vs 21%, P = 0.02) and were more likely to be married (13.2% vs 7.3%, P = 0.02) than the ND group. Treatment retention did not vary by depression status. Hierarchical Linear Modeling found that depressive symptoms decreased comparably across the four treatment groups. Although participation in CM improved drug‐free urines more for patients with MDD than for the ND group (Z = 2.44, P = 0.01), treatment with DMI was significantly more efficacious for the ND group than for the MDD group (Z = −2.89, P = 0.003). These results suggest that patients with MDD may respond better to behavioral treatments such as CM than to desipramine plus buprenorphine. The ND cocaine‐abusing, opiate‐dependent patients may be more responsive to the anticraving effects of DMI.

Treatment of heroin (diamorphine) addiction: current approaches and future prospects.

New pharmacological treatments for heroin (diamorphine) addiction include drugs that reduce opiate withdrawal symptoms and agents that are given during the maintenance phase of treatment. A variety of different types of pharmacological agents (opioid agonists, partial opioid agonists, opioid antagonists and α2-adrenoreceptor agonists) are reviewed and the evidence of their use during managed withdrawal and maintenance are presented.Experimental approaches attempting to reduce the time of opiate withdrawal and to accelerate the transition to abstinence are being developed. The combination tablet of buprenorphine and naloxone that is to be introduced for office-based maintenance is currently undergoing intense evaluation in the US. This new approach may facilitate the expansion of treatment while reducing the potential for medication diversion and intravenous use.

Preliminary study of buprenorphine and bupropion for opioid-dependent smokers.

In this double-blind, placebo-controlled trial, bupropion (BUPRO, 300 mg/day) was compared to placebo (PBO) for the concurrent treatment of opioid and tobacco addiction in 40 opioid-dependent smokers stabilized on buprenorphine (BUPRE, 24 mg/day). Participants received contingent, monetary reinforcement for abstinence from smoking, illicit opioids, and cocaine. Significant differences in treatment retention were observed (BUPRE+BUPRO, 58%; BUPRE+PBO, 90%). BUPRO treatment was not more effective than placebo for abstinence from tobacco, opioids, or cocaine in BUPRE-stabilized patients. These preliminary findings do not support the efficacy of BUPRO, in combination with BUPRE, for the concurrent treatment of opioid and tobacco addiction.

Progesterone effects on cocaine use in male cocaine users maintained on methadone: a randomized, double-blind, pilot study.

Previously, the authors reported that progesterone treatment attenuated reports of cocaine-induced high in male and female cocaine users. In this pilot clinical trial, the authors tested the safety and efficacy of oral progesterone as a treatment for cocaine dependence in methadone-stabilized male cocaine users. This was a 10-week, randomized, double-blind, placebo-controlled trial. Forty-five male methadone-stabilized cocaine users were randomized to receive placebo (n=15) or progesterone (n=30) for 9 weeks. The progesterone dose was gradually increased from 100 mg to 300 mg twice daily by Week 4 and maintained through Week 10. Treatment retention for the clinical trial was 80%, without significant group differences (log rank=2.4, p=.12). Hierarchical linear modeling estimates of obtaining a cocaine positive urine result across 10 weeks showed a very slight reduction in cocaine use for the progesterone group (Z=-2.89, p<.004). The placebo group showed a slight increase in cocaine use from Week 1 to Week 10 (Z=2.72, p<.007). These slopes significantly differed from each other (Z=-3.83, p<.0001). Overall, the placebo group showed significantly lower probability of having a cocaine positive urine result at treatments end (Weeks 9 and 10) compared with the progesterone group (0.60 vs. 0.73; U=4837, p<.04). These preliminary findings do not support the efficacy of progesterone in male cocaine users. The efficacy of progesterone in female cocaine users remains to be determined in future studies.

Cocaine Withdrawal Symptoms Predict Medication Response in Cocaine Users

The purpose of this study was to examine the influence of cocaine withdrawal symptoms on addiction severity and treatment outcomes in methadone stabilized cocaine users who participated in pharmacotherapy trials using gamma-aminobutyric acid (GABA) medications. Subjects who fulfilled DSM-IV cocaine withdrawal criteria (n = 45), compared to those who did not (n = 40), showed a greater increase in cocaine free urines in response to pharmacotherapy with GABA medications. Altogether, our results and previous studies support the clinical utility of cocaine withdrawal symptoms in predicting treatment response to medications, such that low withdrawal severity may predict better treatment response to GABA medications, while high withdrawal severity may predict better response to adrenergic blockers. This hypothesis needs to be tested in prospective clinical trials.

Genetic Association of GABA-A Receptor Alpha-2 and Mu Opioid Receptor with Cocaine Cue-Reactivity: Evidence for Inhibitory Synaptic Neurotransmission Involvement in Cocaine Dependence

BACKGROUND This pilot feasibility study examined the role of genetics in laboratory-induced cocaine craving. METHODS Thirty-four African American, cocaine-depend- ent male subjects underwent a baseline assessment, cue-exposure session, and genetic analysis. Subjects were classified as either cue-reactive or nonreactive. RESULTS Among single nucleotide polymorphism markers in 13 candidate genes examined for association with cocaine cue-reactivity, two were statistically significant: GABRA2 (coding for GABA-A receptor alpha-2 subunit; rs11503014, nominal p= .001) and OPRM1 (coding for mu opioid receptor; rs2236256, nominal p= .03). CONCLUSIONS These pilot results suggest that cocaine craving shows variability among cocaine-dependent subjects, and that GABRA2 and OPRM1 polymorphisms have differential influences on cocaine cue-reactivity, warranting studies in future research.

Intersection of chronic pain treatment and opioid analgesic misuse: causes, treatments, and policy strategies

Treating chronic pain in the context of opioid misuse can be very challenging. This paper explores the epidemiology and potential treatments for chronic pain and opioid misuse and identifies educational and regulation changes that may reduce diversion of opioid analgesics. We cover the epidemiology of chronic pain and aberrant opioid behaviors, psychosocial influences on pain, pharmacological treatments, psychological treatments, and social treatments, as well as educational and regulatory efforts being made to reduce the diversion of prescription opioids. There are a number of ongoing challenges in treating chronic pain and opioid misuse, and more research is needed to provide strong, integrated, and empirically validated treatments to reduce opioid misuse in the context of chronic pain.