Kenneth M. Dürsteler-MacFarland

Assessment of Alcohol Use Among Methadone Maintenance Patients by Direct Ethanol Metabolites and Self‐Reports

BACKGROUND Heavy alcohol consumption may accelerate the progression of hepatitis C (HCV)-related liver disease and/or limit efforts at antiviral treatment. As most of the patients in methadone maintenance treatment (MMT) suffer from hepatitis C infection, this study was conducted to identify the alcohol intake among these patients at a Swiss Psychiatric University Clinic by self-reports and direct ethanol metabolites as biomarkers of ethanol consumption. PATIENTS AND METHODS A convenience sample of 40 MMT patients (15 women, 25 men; median age 39 years) of the total 124 patients was asked and consented to participate in this study. This sample was not different in age, gender distribution, and rate of hepatitis C infection from the total sample. The Alcohol Use Disorders Identification Test (AUDIT) and self-reported ethanol intake during the previous 7 days were assessed. In addition, ethyl glucuronide (EtG) in urine, and fatty acid ethyl esters (FAEEs) and EtG in hair were determined using LC-MS/MS and gas chromatograph/mass spectrometer. The limit of quantitation for UEtG, HEtG, and FAEEs were 0.1 mg/l, 2.3 pg/mg, and 0.1 ng/mg, respectively. RESULTS Fourteen participants reported abstinence from alcohol for the previous 7 days. AUDIT scores were > or =8 in 15 male and >5 in 5 female participants. Direct ethanol metabolites were as follows (median, min, max, standard deviation): UEtG (19 positives; 9.91, 1.38 to 251, 62.39 mg/l); the values of HEtG were 17.65, 0 to 513, 105.62 pg/mg [in 2 cases no material, 8 abstinent (up to 7 pg/mg), 15 social drinkers (up to 50 g per day), and 15 excessive users (>50/60 g/d)]. For the 13 cases, where enough material for additional determination of HFAEEs was available, the values were 0.32, 0 to 1.32, 0.44 ng/mg. Among the 30 HEtG-positive participants, 20 had not reported the corresponding ethanol intake using question 1 (frequency) and 2 (quantity) of the AUDIT. Of the 14 participants reporting no alcohol intake during the previous 7 days, 4 were UEtG-positive. HEtG and AUDIT correlated significantly (r = 0.622, p < 0.0001), but this was not the case for UEtG and self-reported ethanol intake during the previous 7 days. CONCLUSION (1) HEtG identified 20 cases of daily ethanol intake of more than 20 g, that would have been missed by the sole use of question 1 (frequency) and 2 (quantity) of the AUDIT. (2) Using the total score of the AUDIT, HEtG confirmed 10 more cases positive for alcohol intake. (3) Episodic heavy drinking is with 22.5% more frequent than in general population, and (4) of the 14 participants who reported no alcohol intake during the previous 7 days, 4 were UEtG positive. Improved detection of alcohol consumption, which is hazardous or harmful in the context of HCV and opiate dependence, would allow for earlier intervention in this population which is at particular risk of liver disease and fatal respiratory-depressed overdose. The combined use of self-reports and direct ethanol metabolites seems promising.

Serum levels of BDNF are associated with craving in opiate-dependent patients

Preclinical study results suggest that brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) are involved in the modulation of addictive behaviour. We investigated alterations in serum levels of BDNF and GDNF in opiate-dependent patients (28 males) who received diacetylmorphine treatment within a structured opiate maintenance programme. BDNF (T = 2.735, p = 0.009) serum levels were significantly increased in the opiate-dependent patients as compared with healthy controls (21 males), whereas GDNF serum levels (T = 1.425, p = 0.162) did not differ significantly from GDNF serum levels of the healthy controls. BDNF serum levels were significantly associated with craving for heroin (measured by the Heroin Craving Questionnaire (r = 0.420, p = 0.029) and by the General Craving Scale (r = 0.457, p = 0.016), whereas GDNF serum levels were not associated with psychometric dimensions of heroin craving. In conclusion, our results show a positive association between BDNF serum levels and opiate craving in opiate-dependent patients.

Psychobiological responses to drug cues before and after methadone intake in heroin-dependent patients: a pilot study.

Craving and stress frequently drive compulsive heroin use. Although methadone attenuates craving, drug-conditioned stimuli can trigger craving and possibly stress arousal in heroin-dependent patients receiving methadone maintenance. This study investigated drug cue-related craving, affectivity, and cortisol reactivity in 16 methadone-maintained patients before and after daily methadone. Unexpectedly, drug cues significantly increased craving after (t[15]=-4.27, p=0.001), but not before methadone intake. Patients displayed blunted cortisol response after post-methadone drug cues (t[15]=3.05, p=0.008) suggesting dissociated craving and cortisol reactivity after methadone intake of possible clinical relevance.

No association of dopamine receptor sensitivity in vivo with genetic predisposition for alcoholism and DRD2/ DRD3 gene polymorphisms in alcohol dependence

This study sought to examine dopamine receptor sensitivity among alcoholics in vivo and to explore whether this sensitivity might be associated with functional variations of dopamine D2 (DRD2) and D3 (DRD3) receptor genes along with a genetic predisposition for alcoholism as reflected by an alcohol‐dependent first‐degree relative. We analyzed the −141C Ins/Del polymorphism in the promoter region of the DRD2 gene and the Ser9Gly (BalI) polymorphism in exon 1 of the DRD3 gene in 74 alcohol‐dependent Caucasian men with or without genetic predisposition for alcoholism. In vivo dopamine receptor sensitivity was assessed by measuring apomorphine‐induced growth hormone release. A three‐way analysis of variance revealed no significant effects of DRD2, DRD3 genotypes and genetic predisposition on dopamine receptor sensitivity. Given the explorative and preliminary character of this investigation, we cannot provide evidence that in alcohol‐dependent Caucasian men a genetic predisposition for alcoholism along with functional variants of the DRD2 and DRD3 genes are associated with differences in dopamine receptor sensitivity.

Treatment or “high”: Benzodiazepine use in patients on injectable heroin or oral opioids

Benzodiazepine (BZD) use is widespread among opioid-maintained patients worldwide. We conducted a cross-sectional survey to investigate motives and patterns of BZD use and psychiatric comorbidity in a convenience sample of patients (n=193) maintained on oral opioid agonists or diacetylmorphine (DAM). Prolonged BZD use and high-risk behaviors like parenteral use were common. After principal component analysis, motives were divided into those related to negative affect regulation, positive affect regulation (i.e. reward-seeking) and somato-medical problems. Negative affect regulation and somato-medical motives were associated with prolonged use. Psychiatric comorbidity was associated with several self-therapeutic motives, most importantly to lose anxiety. Patients maintained on DAM were more likely to be ex-users of BZD and report high positive affect regulation. Therefore, patients maintained on different agonists may have deviating motives for BZD use, which could be of importance when addressing this issue. Treatment of psychiatric comorbidity, in particular anxiety, depressive and sleeping disorders, may be helpful in reducing BZD use, particularly in patients maintained on oral opioids.

Heroin reduces startle and cortisol response in opioid-maintained heroin-dependent patients

Heroin dependence (HD) is a chronic relapsing brain disorder characterized by a compulsion to seek and use heroin. Stress is seen as a key factor for heroin use. Methadone maintenance and the prescription of pharmaceutical heroin [diacetylmorphine (DAM)] are established treatments for HD in several countries. The present study examined whether DAM‐maintained patients and methadone‐maintained patients differ from healthy controls in startle reflex and cortisol levels. Fifty‐seven participants, 19 of each group matched for age, sex and smoking status, completed a startle session which included the presentation of 24 bursts of white noise while eye‐blink responses to startling noises were recorded. Salivary cortisol was collected three times after awakening, before, during and after the startle session. DAM was administered before the experiment, while methadone was administered afterwards. Both heroin‐dependent patient groups exhibited significantly smaller startle responses than healthy controls (P < 0.05). Whereas the cortisol levels after awakening did not differ across the three groups, the experimental cortisol levels were significantly lower in DAM‐maintained patients, who received their opioid before the experiment, than in methadone‐maintained patients and healthy controls (P < 0.0001). Opioid maintenance treatment for HD is associated with reduced startle responses. Acute DAM administration may suppress cortisol levels, and DAM maintenance treatment may represent an effective alternative to methadone in stress‐sensitive, heroin‐dependent patients.

A randomized, controlled, pilot trial of methylphenidate and cognitive-behavioral group therapy for cocaine dependence in heroin prescription.

Abstract Cocaine dependence has proved difficult to treat, whether it occurs alone or in combination with opiate dependence. No intervention has been demonstrated to be uniquely effective. Patients might benefit most from combined pharmacotherapeutic and psychotherapeutic interventions. The present study sought to evaluate the feasibility, tolerability, and efficacy of methylphenidate (MP) and cognitive-behavioral group therapy (CBGT) for cocaine dependence in diacetylmorphine-maintained patients. Sixty-two cocaine-dependent diacetylmorphine-maintained patients participated in a dual-site, double-blind, placebo-controlled pilot trial with 4 treatment conditions. The participants were randomly assigned to receive MP or a placebo each combined with either CBGT or treatment as usual for 12 weeks. Methylphenidate 30 mg and a placebo in identical capsules were administered onsite twice daily under supervision in a fixed-dose regimen without titration. Manual-guided CBGT consisted of 12 weekly sessions. Participation in the CBGT sessions was voluntary. Primary outcome measures were retention in pharmacologic treatment, cocaine-free urine samples, self-reported cocaine use, and adverse effects. Urine screens were performed thrice weekly. Seventy-one percent of the participants completed the study protocol. Methylphenidate was well tolerated with similar retention rates compared with the placebo. No serious adverse effects occurred. No difference in cocaine-free urine screens was found across the 4 treatment groups. Self-reported cocaine use was reduced in all 4 study groups. Methylphenidate and CBGT did not provide an advantage over a placebo or treatment as usual in reducing cocaine use. There were no signs of additive benefits of MP and CBGT. Because of the small sample size, the results are preliminary.

A Systematic Review Comparing Cognitive-Behavioral Therapy and Contingency Management for Cocaine Dependence

The main objective of this review was to compare the effectiveness of cognitive-behavioral therapy and contingency management for cocaine dependence. Contingency management alone reliably reduced cocaine use during active treatment in all cited trials, whereas the positive effect of cognitive-behavioral therapy emerged after treatment in 3 of 5 trials. Synergistic effects of the combination of contingency management plus cognitive-behavioral therapy are shown in 2 trials, but another 3 trials found no additive effects. Positive, rapid, and enduring effects on cocaine use are reliably seen with contingency management interventions, whereas measurable effects of cognitive-behavioral therapy emerge after treatment and are not as reliable as effects with contingency management.

A Functional Polymorphism in the Promoter Region of the Monoamine Oxidase A Gene Is Associated with the Cigarette Smoking Quantity in Alcohol-Dependent Heavy Smokers

Tobacco smoking represents a leading cause of morbidity and mortality with a strong dose-response relation between the amount of smoking and the risks of tobacco-related diseases and death. The quantity that is smoked is determined predominantly by genetic factors. The present study examined whether there is an association between the quantity of cigarettes smoked and length variation of a functional 30-bp repeat polymorphism in the promoter region of the monoamine oxidase A (MAO-A) gene. The number of 30-bp repeats, which is associated with enzyme activity was assessed in 121 Caucasian men suffering from both alcohol and tobacco dependence. Analysis revealed that the highly active long allele (4 repeat) is associated with a significantly greater amount of cigarette smoking in comparison with the less active short allele (3 repeat). In a logistic regression model (dichotomized), smoking quantity was significantly predicted by MAO-A genotype while no other variable (age, height, body weight, frequency of smoking, quantity and frequency of alcohol consumption) met the significance level. Since tobacco smoke is a potent inhibitor of MAO-A, this result could be regarded as a genotype-related dosage effect. Taken together, in alcohol-dependent heavily smoking men there is evidence for a MAO-A gene-associated effect on the quantity that is smoked as reflected by the daily number of cigarettes consumed.

A randomized, controlled trial of combined cognitive-behavioral therapy plus prize-based contingency management for cocaine dependence

BACKGROUND Cocaine has become one of the drugs of most concern in Switzerland, being associated with a wide range of medical, psychiatric and social problems. Available treatment options for cocaine dependence are rare. The study sought to compare combined prize-based contingency management (prizeCM) plus cognitive-behavioral therapy (CBT) to CBT alone in cocaine-dependent patients. METHODS Sixty cocaine-dependent patients participated in a randomized, controlled trial with two treatment conditions. The participants were randomly assigned to the experimental group (EG; n = 29), who received CBT combined with prizeCM, or to the control group (CG; n = 31), who received CBT only during 24 weeks. The primary outcome measures were retention, at least 3 consecutive weeks of cocaine abstinence, the maximum number of consecutive weeks of abstinence and proportions of cocaine-free urine samples during the entire 24-week and at 6-month follow-up. RESULTS Sixty-three percent of the participants completed the study protocol. Participants in both groups significantly reduced cocaine use over time. Overall, no difference in cocaine-free urine screens was found across the two treatment groups, except at weeks 8, 9, 10, 17 and 21 in favor of the EG. CONCLUSIONS The addition of prizeCM to CBT seems to enhance treatment effects, especially in the early treatment period, supporting results from previous studies. Both the combined intervention and CBT alone, led to significant reductions in cocaine use during treatment and these effects were sustained at 6-month follow-up. These findings underline the importance in implementing CM and CBT interventions as treatment options for cocaine dependence in the European context.