Anders Hammarberg

Naltrexone for the Treatment of Amphetamine Dependence: A Randomized, Placebo-Controlled Trial

OBJECTIVE Currently there is no approved pharmacotherapy for amphetamine dependence. Recent human laboratory studies have demonstrated that naltrexone modulates some of the reinforcing effects of amphetamine. The aim of this study was to investigate the efficacy of naltrexone in comparison with placebo in reducing relapse to amphetamine use in amphetamine-dependent patients. METHOD Eighty patients who met DSM-IV criteria for amphetamine dependence were randomized to 12 weeks of double-blind naltrexone (50 mg) or placebo treatment. Patients visited the clinic twice weekly to receive medication and relapse prevention therapy and leave urine samples, which were analyzed for drug toxicology and for assessing adherence to medication via detection of naltrexones metabolite (6-beta-naltrexol). The main outcome measure was abstinence from amphetamine use, as indicated by the total number of negative amphetamine urine samples during 12 weeks of treatment. All missing urine samples were defined for the analysis as positive for amphetamine. RESULTS Overall, 55 patients (68.8%) completed the trial. The intention-to-treat analysis showed that the naltrexone group had a significantly higher number of amphetamine-negative urine samples compared with the placebo group. Survival analyses showed that the treatment groups differed in rate of continuous abstinence, in both the intention-to-treat and completer samples, in favor of naltrexone treatment. There was a significant reduction in craving levels and self-reported consumption of amphetamine in the naltrexone group compared with the placebo group. Treatment with naltrexone was well tolerated in this sample. CONCLUSIONS This trial demonstrated the efficacy of naltrexone in reducing amphetamine use in amphetamine-dependent individuals.

Naltrexone Attenuates the Subjective Effects of Amphetamine in Patients with Amphetamine Dependence

Amphetamine abuse and dependence is a global health concern with a collateral increase in medical and social problems. Although some of the neurobiological mechanisms underlying amphetamine dependence and its devastating effects in humans are known, the development of rational and evidence-based treatment is lagging. There is evidence from preclinical studies suggesting that the endogenous opioid system plays a role in mediating some of the behavioral and neurochemical effects of amphetamine in a variety of controlled settings. In the present study we assessed the effects of naltrexone, an opioid antagonist (50 mg) on the subjective physiological and biochemical response to dexamphetamine (30 mg) in 20 amphetamine-dependent patients. Patients received naltrexone/amphetamine followed by placebo/amphetamine, 1 week apart in a randomized double-blind placebo-controlled design. The primary objective of the study was to evaluate the effect of pretreatment with naltrexone on the subjective response to amphetamine, using a Visual Analog Scale. The secondary objective was to investigate the effects of naltrexone on physiological and biochemical responses to amphetamine, as measured by changes in blood pressure, heart rate, skin conductance, and cortisol. Naltrexone significantly attenuated the subjective effects produced by dexamphetamine in dependent patients (p<0.001). Pretreatment with naltrexone also significantly blocked the craving for dexamphetamine (p<0.001). There was no difference between the groups on the physiological measures. The results suggest that the subjective effects of amphetamine could be modulated via the endogenous opioid system. The potential of naltrexone as an adjunct pharmaceutical for amphetamine dependence is promising.

Phosphatidylethanol is Superior to Carbohydrate-Deficient Transferrin and γ-Glutamyltransferase as an Alcohol Marker and is a Reliable Estimate of Alcohol Consumption Level.

BACKGROUND In clinical practice as well as research situations, it is of great importance to get reliable information about a patients alcohol consumption. The aim of the study was to investigate the correlation of alcohol biomarkers (phosphatidylethanol [PEth], carbohydrate-deficient transferrin [CDT], γ-glutamyltransferase, aspartate aminotransferase, and alanine aminotransferase) to retrospective as well as diary-based alcohol self-reports and to examine whether it is possible to correlate a biomarker result to a more precise level of alcohol consumption. METHODS One hundred and sixty alcohol-dependent patients were included in a randomized, placebo-controlled clinical trial of pharmacotherapy for alcohol dependence, of which 115 (76 men and 39 women) completed the study. Retrospective alcohol consumption data were collected at baseline, and alcohol diaries were used during the study. Blood samples for determination of alcohol biomarkers were collected on 5 occasions during the study. RESULTS PEth and CDT showed a better correlation with alcohol consumption documented in the diary (PEth rs = 0.56 and CDT rs = 0.35) than with retrospective consumption data (PEth rs = 0.23 and CDT rs = 0.22). An even higher correlation (rs = 0.63) was seen between the 2 alcohol biomarkers PEth and CDT. At all consumption levels, PEth had the highest sensitivity of all biomarkers studied. CONCLUSIONS PEth was the biomarker with the best correlation to self-reported alcohol consumption. PEth was superior to CDT owing to its substantially higher sensitivity but also due to its closer correlation to self-report. PEth values can be translated into an approximate level of alcohol consumption and PEth appears to be a more reliable measure of alcohol consumption than self-reports.

Amphetamine Dependence and Co-Morbid Alcohol Abuse: Associations to Brain Cortical Thickness

BackgroundLong-term amphetamine and methamphetamine dependence has been linked to cerebral blood perfusion, metabolic, and white matter abnormalities. Several studies have linked methamphetamine abuse to cortical grey matter reduction, though with divergent findings. Few publications investigate unmethylated amphetamines potential effects on cortical grey matter. This work investigated if amphetamine dependent patients showed reduced cortical grey matter thickness. Subjects were 40 amphetamine dependent subjects and 40 healthy controls. While all subjects were recruited to be free of alcohol dependence, structured clinical interviews revealed significant patterns of alcohol use in the patients. Structural magnetic resonance brain images were obtained from the subjects using a 1.5 Tesla GE Signa machine. Brain cortical thickness was measured with submillimeter precision at multiple finely spaced cortical locations using semi-automated post-processing (FreeSurfer). Contrast analysis of a general linear model was used to test for differences between the two groups at each cortical location. In addition to contrasting patients with controls, a number of analyses sought to identify possible confounding effects from alcohol.ResultsNo significant cortical thickness differences were observed between the full patient group and controls, nor between non-drinking patients and controls. Patients with a history of co-morbid heavy alcohol use (n = 29) showed reductions in the superior-frontal right hemisphere and pre-central left hemisphere when compared to healthy controls (n = 40).ConclusionsAmphetamine usage was associated with reduced cortical thickness only in patients co-morbid for heavy alcohol use. Since cortical thickness is but one measure of brain structure and does not capture brain function, further studies of brain structure and function in amphetamine dependence are warranted.

Urinary Ethyl Glucuronide and Ethyl Sulfate Testing for Recent Drinking in Alcohol-Dependent Outpatients Treated with Acamprosate or Placebo

AIMS Ethyl glucuronide (EtG) and ethyl sulfate (EtS) are sensitive and specific biomarkers for recent alcohol ingestion. This study compared urinary EtG and EtS measurement with self-reports for detection of prior drinking in alcohol-dependent outpatients treated with the anti-craving medication acamprosate or placebo. METHODS Alcohol-dependent outpatients (26 women, 30 men) were randomized to 21 days of oral acamprosate (2 g/day) or placebo treatment in a double-blind design. They were instructed to refrain from drinking during the study. Return visits to the ward for blood and urine sampling and filling out questionnaires were made on Day 7, 14 (urine sample optional) and 22 (urine sample mandatory). EtG and EtS were determined by liquid chromatography-mass spectrometry. RESULTS On the first day (Day 0), 72% of all patients (acamprosate 65%, placebo 78%) tested positive for recent drinking according to urinary EtG (reporting limit ≥ 0.5 mg/l) and EtS (≥ 0.1 mg/l). On the final day (Day 22), the frequency of positive tests was significantly reduced to 30% in the acamprosate group (P = 0.0374) and 33% for placebo (P = 0.0050). However, there was no difference between the treatment groups. When both groups were combined, the EtG (P = 0.025) and EtS (P = 0.015) concentrations were lower on the final day. Altogether, EtG and EtS were detected in 76 of 156 (49%) urine samples. When drinking in the day before sampling was admitted, 93% of urines tested positive; when drinking was denied, still 28% of the samples were positive. CONCLUSION These results confirmed the value of urinary EtG and EtS as reliable indicators of recent drinking during outpatient treatment of persons with alcohol-related problems, and as objective outcome measures when evaluating new alcohol treatment strategies and pharmacotherapies.

Varenicline for Treatment of Alcohol Dependence: A Randomized, Placebo-Controlled Trial

BACKGROUND Alcohol dependence is a devastating illness affecting a large population, and new pharmacological treatments with good efficacy are greatly needed. One potential candidate is varenicline, a smoking cessation agent with partial agonist action at α4 β2 nicotinic acetylcholine receptors. METHODS A total of 160 subjects, 30 to 70 years of age, fulfilling DSM-IV criteria for alcohol dependence without any serious physical or mental disorders, were recruited through advertisement at 3 university clinics in Sweden during March 2009 to January 2011. After a 2-week placebo run-in period, subjects received 2 mg varenicline daily (titrated from 0.5 mg during first week) or placebo for 12 weeks in a double-blind manner. RESULTS The primary outcome was the proportion of heavy drinking days, measured by self-reported alcohol consumption. Primary and secondary outcomes were calculated as a mean over the 10-week steady-state active treatment period. In the primary outcome analysis, no effect of varenicline over placebo was found (p = 0.73 for the intention to treat [ITT] and 0.92 for per protocol [PP]). Secondary outcome analysis found a significant reduction of specific alcohol marker phosphatidylethanol (PEth) in the blood in the varenicline group compared to placebo (p = 0.02 ITT). Craving (p = 0.048 PP) and Alcohol Use Disorders Identification Test (AUDIT) scores (p = 0.015 ITT) were also reduced in the active treatment group. PEth more strongly correlated with self-reported alcohol consumption than carbohydrate-deficient ttransferrin and γ-glutamyl transferase, and correlation coefficients were higher in the varenicline group than in the placebo group for all markers. CONCLUSIONS Although the results of the main outcome of this study did not support an effect of varenicline in alcohol-dependent individuals, the secondary analyses of PEth, craving and AUDIT score support an effect of varenicline on alcohol consumption. The disclosure of a treatment effect and the lack of a clear placebo effect when using PEth as outcome variable, together with a nonsymmetric bias associated with self-reported data, strongly argue for using the specific biomarker PEth in studies of treatments of alcohol dependence.

Cerebellar volumes in men with schizophrenia and alcohol dependence

Abstract  The aim of the present study was to investigate the variation in cerebellar morphology in schizophrenia and alcohol dependence. Volumetric measurements of cerebellar structures were performed using magnetic resonance imaging in 17 men with schizophrenia, nine men with alcohol dependence, and 18 healthy men. Schizophrenia patients had smaller volumes of the posterior superior vermis, while alcohol‐dependent patients had smaller volumes of both the anterior and the posterior superior vermis compared with controls. The groups were not significantly different with respect to cerebellar hemisphere volumes. The results provide indications for differential morphological abnormalities of the cerebellar vermis in patients with schizophrenia and alcohol dependence.

Acamprosate determinations in plasma and cerebrospinal fluid after multiple dosing measured by liquid chromatography-mass spectroscopy: a pharmacokinetic study in healthy volunteers.

The central nervous system-active medication acamprosate has been shown to modulate alcohol-related behavior in both preclinical and clinical studies. Although commonly used in the treatment of alcohol dependence, there are still unanswered questions concerning the pharmacokinetic properties of acamprosate. The aims of the present study were to 1) to validate liquid chromatography-mass spectrometry as a method to study the presence of acamprosate in plasma and cerebrospinal fluid (CSF) in humans; and 2) validate previous results on clinically important pharmacokinetic data for acamprosate. In an open label, single-site design, 13 healthy males and females were recruited to 22 days of oral acamprosate treatment (1998 mg/day). Subjects provided in all 256 plasma samples for analysis at regular intervals at Day 1, 7, 14, and 22 of treatment. On Day 22, subjects also left a sample of CSF for measurement of acamprosate. The results showed that steady-state level of acamprosate was accomplished within 5 days after the start of treatment and remained fairly stable for 2 to 3 days after termination of treatment. Variations in plasma concentrations corresponded to earlier studies and did not exceed those for comparable pharmacotherapeutic agents. Acamprosate concentrations in the CSF were below the limit of quantification, ie, estimated concentrations between 9 and 33 ng/mL. Plasma concentrations were more than 25 times higher than in lumbar CSF. The low CSF levels seen after 3 weeks of treatment may provide an explanation to the delay in therapeutic effect noticed in treatment studies on acamprosate. A longer duration of treatment might be necessary to obtain clinically significant brain levels of acamprosate. In summary, the present study validated liquid chromatography-mass spectrometry as a method for assessment of compliance to acamprosate treatment. Furthermore, the results suggest that the mechanism of action of acamprosate needs to be further explored with regard to the peripheral actions of the drug.

The effect of acamprosate on alcohol craving and correlation with hypothalamic pituitary adrenal (HPA) axis hormones and beta-endorphin

Acamprosate is a widely utilized, efficacious treatment for relapse prevention in alcohol dependent patients. The mechanism of acamprosate action is hypothesized to be by modulation of craving responses. Previous research has suggested that acamprosate may affect the hypothalamic pituitary adrenal (HPA) axis as well as beta-endorphin. The aim of the present study was to investigate if acamprosate attenuates alcohol craving following a short-term treatment, and if craving and drinking measures are correlated to changes in HPA-axis hormones and beta-endorphin. In a double-blind design, 56 alcohol dependent treatment seeking patients were randomized to 21 days of either acamprosate (1998 mg/day) or placebo treatment. Subjective, physiological and biological measurements were recorded at inclusion and on day 21. The results showed that acamprosate treated patients showed significantly reduced craving compared to placebo. Further, a significant correlation was shown between craving and alcohol consumption during study. No changes in hormonal levels were found in acamprosate treated patients compared to placebo.

Incidence and spontaneous clearance of hepatitis C virus (HCV) in people who inject drugs at the Stockholm Needle Exchange-Importance for HCV elimination

The major transmission route for hepatitis C virus (HCV) is through sharing of unsterile injection equipment among people who inject drugs (PWID). The WHO strategy for HCV elimination by 2030 proposes increased efforts to treat PWID populations that drive the HCV epidemic. Among participants in the Stockholm needle exchange programme (NEP), the HCV prevalence is 60%. We aimed to study HCV incidence, spontaneous HCV clearance rate, and predictors associated with new HCV infections and reinfections in NEP participants. All 2320 patients enrolled in the programme between 8 April 2013 and 23 September 2016 were tested for HCV at baseline, and responded to a questionnaire regarding sociodemographic data and injection risk behaviour. Tests for HCV were repeated at an interval of 3‐6 months. The anti‐HCV prevalence in the NEP participants at baseline was 77%, and the prevalence of HCV RNA was 57%. 24% of the anti‐HCV positive were HCV RNA negative with a spontaneously cleared HCV infection. The overall HCV incidence rate was 22/100 PY. The HCV incidence rate in the HCV naive group was 26/100 PY, and in the spontaneously cleared group 19/100. Although there were no significant differences in becoming HCV infected between the two groups (31% vs 29%), the rate of spontaneous HCV clearance was significantly lower in the HCV naive group, 20% vs 44%, (P < 0.05). A high HCV incidence rate was noted among the PWID indicating that treatment needs to be scaled up in conjunction with harm reduction measures to achieve HCV elimination goals set by WHO. This includes high coverage needle exchange programmes and effective addiction treatment for substance users, including opiate substitution treatment.