Library Watch - On Medical Aspects

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...on medical aspects

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Summer 2006

A randomized placebo-controlled trial of gabapentin for cocaine dependence.

Bisaga A; Aharonovich E; Garawi F; Levin FR; Rubin E; Raby WN et al. Drug and Alcohol Dependence 81(3): 267-274, 2006. (41 refs.)
Background: In laboratory animals, augmentation of GABA neurotransinission results in inhibition of cocaine self-administration and inhibition of reinstatement to cocaine-seeking behaviors. If parallel effects were observed in humans, GABA-ergic medication should be effective both in the abstinence-induction as well as in the relapse-prevent ion phase of cocaine dependence treatment. Gabapentin is an anticonvulsant medication that increases human brain GABA levels. We evaluated the safety and efficacy of gabapentin combined with relapse-prevention therapy in the treatment of cocaine-dependent individuals. Design: The study involved 129 individuals with cocaine dependence. Of the 99 participants, who were randomized into a double-blind trial 88% were males, 66% were minorities and with an average age of 39 years (range 22-58 years). After 2 weeks of placebo lead-in, participants were randomized to receive either gabapentin 3200 mg (1600 in,, bid) or placebo for 12 weeks, followed by 2 weeks of placebo lead-out. Prior to randomization, participants were stratified into four groups based on the principal route of cocaine use (smokers versus intranasal users) and the level of cocaine use during the 2 weeks of lead-in (high level versus low level). Throughout the 16 weeks study, participants received weekly individual relapse-prevention therapy. The outcome measures included: days of cocaine use and a binary indicator of abstinence based on urine toxicology test, self-reported cocaine craving and retention in treatment. Results: Forty-nine percent of randomized patients completed 12 weeks of the trial. Retention did not differ by treatment group but cocaine-smokers dropped out of treatment at a significantly faster rate than intranasal users. For the entire sample, odds of cocaine use over the course of the study did not differ between gabapentin- and placebo-treated individuals. There was a significant difference in the odds of cocaine use between high and low-use groups, with the odds in high-use groups decreasing over time and odds in the low-use groups gradually increasing over the course of the study, such that by the end of the study low and high users were similarly likely to use cocaine. In the low-use group, there was a non-significant trend suggesting that gabapentin-treated subjects had more favorable outcome compared to placebo-treated individuals. There was no treatment effect on abstinence rates, craving or other substance use. Gabapentin at 3200 ingday was very well tolerated in this group of cocaine-dependent participants. Conclusions: When combined with weekly individual relapse-prevention therapy-abapentin 1600 mg bid was no more effective than placebo in the treatment of cocaine dependence. When reviewed in conjunction with other published studies, gabapentin and other GABA enhancing anticonvulsant medications may deserve further study as relapse-preventive agents in cocaine-dependent individuals who achieve abstinence early in treatment.

Alcohol dehydrogenase 1C*1 allele is a genetic marker for alcohol-associated cancer in heavy drinkers.

Homann N; Stickel F; Konig IR; Jacobs A; Junghanns K; Benesova M et al. International Journal of Cancer 118(8): 1998-2002, 2006. (34 refs.)
Chronic alcohol consumption is associated with an increased risk for upper aerodigestive tract cancer and hepatocellular carcinoma. Increased acetaldehyde production via alcohol dehydrogenase (ADH) has been implicated in the pathogenesis. The allele ADHIC*1 of ADH1C encodes for an enzyme with a high capacity to generate acetaldehyde. So far, the association between the ADH1C*1 allele and alcohol-related cancers among heavy drinkers is controversial. ADH1C genotypes were determined by polymerase chain reaction and restriction fragment length polymorpism in a total of 818 patients with alcohol-associated esophageal (n = 123), head and neck (n = 84) and hepatocellular cancer (n = 86) as well as in patients with alcoholic pancreatitis (n = 117), alcoholic liver cirrhosis (n = 217), combined liver cirrhosis and pancreatitis (n 17) and in alcoholics without gastrointestinal organ damage (n 174). The ADH1C*1 allele and genotype ADH1C*1/1 were significantly more frequent in patients with alcohol-related cancers than that in individuals with nonmalignant alcohol-related organ damage. Using multivariate analysis, ADH1C*1 allele frequency and rate of homozygosity were significantly associated with an increased risk for alcohol-related cancers (p < 0.001 in all instances). The odds ratio for genotype ADH1C*1/1 regarding the development of esophageal, hepatocellular and head and neck cancer were 2.93 (CI, 1.84-4.67), 3.56 (CI, 1.33-9.53) and 2.2 (Cl, 1.11-4.36), respectively. The data identify genotype ADH1C*1/1 as an independent risk factor for the development of alcohol-associated tumors among heavy drinkers, indicating a genetic predisposition of individuals carrying this genotype.

An outbreak of hepatitis B virus infection among methamphetamine injectors: The role of sharing injection drug equipment.

Vogt TM; Perz JF; Van Houten CK; Harrington R; Hansuld T; Bialek SR et al. Addiction 101(5): 726-730, 2006. (15 refs.)
Aim: To identify risk factors for acute hepatitis B virus (HBV) infection among Wyoming methamphetamine injectors. Design: A case-control study conducted in the setting of an outbreak. Setting A county in central Wyoming, United States. Participants: Cases were identified through surveillance and contact tracing and were defined as Natrona County, Wyoming, residents who were either symptomatic or confirmed serologically to be acutely infected with HBV during January-August, 2003. Controls were susceptible to HBV infection. All participants identified themselves as methamphetamine injectors. Measurements: Participants were administered a survey that inquired about risk factors for HBV infection, including drug use practices and sexual behaviors. Controls were also tested serologically for acute HBV infection. Findings: Among the 18 case-patients and 49 controls who participated in the study, sharing water used to prepare injections and/or rinse syringes was associated with HBV infection (94% of case-participants versus 44% of controls; OR = 21.9, 95% CI: 2.7, 177.8), as was sharing cotton filters (89% of case-participants versus 52% of controls; OR = 7.4, 95% CI: 1.5, 35.6); sharing syringes was not statistically associated. In logistic regression models adjusted for age, sex, and interview site, sharing rinse water and sharing cotton remained statistically associated. Conclusions: Methamphet-amine use has become increasingly prevalent in the United States. Our findings highlight the need for awareness of risks associated with injection drug use and sharing behaviors. Enhanced hepatitis B vaccination programs and educational campaigns that target methamphetamine injectors specifically, including those living in rural areas, should be developed and implemented.

Coffee and health: A review of recent human research. (review).

Higdon JV; Frei B. Critical Reviews in Food Science and Nutrition 46(2): 101-123, 2006. (290 refs.)
Coffee is a complex mixture of chemicals that provides significant amounts of chlorogenic acid and caffeine. Unfiltered coffee is a significant source of cafestol and kahweol, which are diterpenes that have been implicated in the cholesterol-raising effects of coffee. The results of epidemiological research suggest that coffee consumption may help prevent several chronic diseases, including type 2 diabetes mellitus, Parkinson's disease and liver disease (cirrhosis and hepatocellular carcinoma). Most prospective cohort studies have not found coffee consumption to be associated with significantly increased cardiovascular disease risk. However, coffee consumption is associated with increases in several cardiovascular disease risk factors, including blood pressure and plasma homocysteine. At present, there is little evidence that coffee consumption increases the risk of cancer. For adults consuming moderate amounts of coffee (3-4 cups/d providing 300-400 mg/d of caffeine), there is little evidence of health risks and some evidence of health benefits. However, some groups, including people with hypertension, children, adolescents, and the elderly, may be more vulnerable to the adverse effects of caffeine. In addition, currently available evidence suggests that it may be prudent for pregnant women to limit coffee consumption to 3 cups/d providing no more than 300 mg/d of caffeine to exclude any increased probability of spontaneous abortion or impaired fetal growth.

Decreased frontal white-matter volume in chronic substance abuse.

Schlaepfer TE; Lancaster E; Heidbreder R; Strain EC; Kosel M; Fisch HU et al. International Journal of Neuropsychopharmacology 9(2): 147-153, 2006. (51 refs.)
There is quite a body of work assessing functional brain changes in chronic substance abuse, Much less is known about structural brain abnormalities in this patient population. In this study we used magnetic resonance imaging (MRI) to determine if structural brain differences exist in patients abusing illicit drugs compared to health), controls. Sixteen substance abusers who abused heroin, cocaine and cannabis but not alcohol and 16 age-, sex- and race-matched controls were imaged on a MRI scanner. Contiguous, 5-mm-thick axial slices were acquired with simultaneous T-2 and proton density sequences. Volumes were estimated for total grey and white matter, frontal grey and white matter, ventricles, and CSF using two different methods: a conventional segmentation and a stereological method based on the Cavalieri principle. Overall brain volume differences were corrected for by expressing the volumes of interest as a percentage of total brain volume. Volume measures obtained with the two methods were highly correlated (r = 0.65, p < 0.001). Substance abusers had significantly less frontal white-matter volume percentage than controls. There were no significant differences in any of the other brain volumes measured. This difference in frontal lobe white matter might be explained by a direct neurotoxic effect of drug use on white matter, a pre-existing abnormality in the development of the frontal lobe or a combination of both effects. This last explanation might be compelling based on the fact that newer concepts on shared aspects of some neuropsychiatric disorders focus on the promotion and inhibition of the process of myelination throughout brain development and subsequent degeneration.

Drinking patterns are associated with variations in atherosclerotic risk factors in French men.

Rouillier P; Bertrais S; Daudin JJ; Bacro JN; Hercberg S; Boutron-Ruault MC. European Journal of Nutrition 45(2): 79-87, 2006. (38 refs.)
Background: While a relationship between alcohol and cardiovascular risk factors is well established, data suggest that the type of alcoholic beverage could modulate this relationship. Aim of the study To determine whether drinking patterns modulate the relationship between alcohol and cardiovascular risk factors. Methods We tested the relationship between preference of alcoholic beverages and atherosclerotic risk factors in a cross-sectional study of 2,126 men. A hierarchical clustering method determined six drinking patterns, 'low drinkers', 'high quality wines', 'beer and cider', 'digestives', 'local wines', and 'table wines', according to the preferential intake of alcoholic beverages. Logistic models estimated the relative risk of abnormal markers in the drinking patterns compared with low drinkers. Unadjusted estimates investigated the relationship with the cluster as a group, while adjustment on alcohol, nutritional and socio-demographic factors investigated the relationship with the preference of alcoholic beverage in itself. Results Abstainers had high total plasma homocysteine (tHcy), even after full adjustment (odds ratio (OR) = 1.6, 95% confidence interval (CI): 1.0, 2.8). Drinkers of high quality wine had low lipoprotein( a), high tHcy and high body mass index; beer and cider drinkers had high tHcy and waist circumference. Drinkers of digestives had high triacylglycerol; after adjustment they were at risk of low apolipoprotein A-I (OR = 3.1, 95% CI: 1.2, 7.3), and high tHcy (OR = 4.9, 95% CI: 1.2, 33.3). Local wines drinkers were similar to low drinkers. Table wine drinkers had high apolipoprotein B, high triacylglycerol, and high waist-to-hip ratio. Conclusions Our data suggest that preference of alcoholic beverage could indicate groups at specific risks of atherosclerotic disease.

Drugs of abuse testing in meconium. (review).

Gareri J; Klein J; Koren G. Clinica Chimica Acta 366(1-2): 101-111, 2006. (84 refs.)
Prenatal substance abuse is an ongoing concern with significant impact on neonatal health and development across socioeconomic lilies. Meconium, passed by neonates during their first post-natal bowel movements, is a matrix unique to the developing fetus and contains a long history of prenatal metabolism. Over the last two decades, the use of meconium as a matrix for assessing prenatal exposure to drugs of abuse has yielded methods exhibiting higher sensitivity, easier collection, and a larger window of detection than traditional matrices. Recently, a method has been developed for the analysis of fatty acid ethyl esters in meconium as a biomarker of fetal alcohol exposure, potentially facilitating the future diagnosis of Fetal Alcohol Spectrum Disorder in situations where gestational alcohol consumption history is unknown. Screening for prenatal exposure to illicit and abused licit drugs in meconium is possible by use of a variety of immunoassay methods with conformational analysis usually occurring by GCMS or LCMS. In spite of increased sample preparation time relative to blood and urine, the long metabolic history, coupled with the case and wide window of collection of meconium make it the ideal matrix for determining fetal drug exposure.

Family history of alcoholism and cognitive recovery in subacute withdrawal.

Moriyama Y; Muramatsu T; Kato M; Mimura M; Kashima H. Psychiatry and Clinical Neurosciences 60(1): 85-89, 2006. (23 refs.)
A family history of alcoholism has been demonstrated to be an important factor affecting cognitive function. However, no studies have yet been conducted to compare cognitive recovery of family history-positive (FH+) and family history-negative (FH-) alcoholics in the subacute withdrawal period. To tackle this problem, a neuropsychological test battery consisting of six computerized tests was administered to 19 FH+ and 20 FH- alcoholics at 2 and 7 weeks after abstinence. At 2 weeks after abstinence, overall performance of both FH+ and FH- groups was significantly poorer than that of healthy controls. At 7 weeks, these performances tended to recover, but in Trail Making A and Figure Position, performances of FH+ alcoholics remained worse than those of controls, while those of FH- alcoholics did not. Thus cognitive recovery during the subacute withdrawal period was worse among FH+ alcoholics than FH- alcoholics, and this finding should be considered when planning alcohol rehabilitation programs.

Fentanyl abuse and dependence: Further evidence for second hand exposure hypothesis.

Gold MS; Melker RJ; Dennis DM; Morey TE; Bajpai LK; Pomm R et al. Journal of Addictive Diseases 25(1): 15-21, 2006. (20 refs.)
We have proposed a novel hypothesis regarding the potential role of occupational or second-hand exposure in physician substance use, abuse, and addiction. While only 5.6% of licensed physicians in Florida are anesthesiologists, nearly 25% of physicians followed for substance abuse/dependence are anesthesiologists. When we sort by drug of choice, anesthesiologists have more opioid abuse and dependence than other physicians and appropriate controls. Abuse of one opioid, fentanyl, appears to be increasing and has been noted among the State of Florida's causes of opioid deaths. Fentanyl and sufentanyl are commonly administered highly potent opioid analgesics, as much as 80-800 times as potent as morphine. We have recent data from the State of Florida impaired physicians database, which has allowed us to categorize all fentanyl abusing and/or dependent physicians. Just knowing that a physician abuses fentanyl gives you a good clue as to their specialty; 75% are anesthesiologists! While drug abuse researchers, oncologists and others who handle drugs of abuse everyday, have no greater incidence of opioid abuse or dependence, anesthesiologists are at the top of every list. Can this be due to just access and stress? We have proposed an alternative hypothesis of second hand exposure. To test this hypothesis, we developed a sensitive LC/MS/MS assay to measure the intravenous anesthetic and analgesic agents, propofol and fentanyl in air. Not only did we detect propofol and fentanyl in cardiovascular surgery operating room air, we also found the highest concentrations were close to the patient's mouth where anesthesiologists work for hours. Like tobacco, second hand opioid exposure can sensitize and change the brain making abuse, dependence and behavioral disorders more likely. Thus environmental exposure and sensitization may be an important risk factor in physician addiction. Second hand exposure may affect treatment outcome and explain anesthesiologist's inability to return to work in the operating room. We are developing an animal model for second hand exposure and additional studies of the operating room and cardiac anesthesiologists are underway.

Effect of opioid substitution therapy on alcohol metabolism.

Clark NC; Dietze P; Lenne MG; Redman JR. Journal of Substance Abuse Treatment 30(3): 191-196, 2006. (35 refs.)
Forty opioid substitution patients (methadone, n = 14; LAAM, n = 14; and buprenorphine, n = 12) who were participating in a study on the impact of opiate substitution treatment on driving ability and 22 non-opiate-using control subjects were administered 14.7 g/70 kg of alcohol in two separate sessions, one 2-3 hours before opioid pharmacotherapy dosing and the other 1-2 hours after dosing. The mean blood alcohol concentration (BAC) in the post-opioid dose session was significantly lower than that in the pre-opioid dose session (p < .05). There was a significant effect of experimental group (LAAM, methadone, buprenorphine, or control) on BAC in sessions conducted 1-2 hours after the opioid substitution dose (p < .01). There was a trend for a reduced effect of experimental group on BAC in the pre-opioid substitution dose session (p = .06). The BAC of non-opioid substitution control subjects was significantly higher than that of the LAAM (before and after LAAM dosing) and methadone (after methadone dosing; p < .05) patients. These findings provide evidence for the first time of an interaction between opiates and alcohol in humans that is strongest at the time of peak opiate plasma levels in the hours after opioid dosing.

High methadone dose significantly reduces cocaine use in methadone maintenance treatment (MMT) patients.

Peles E; Kreek MJ; Kellogg S; Adelson M. Journal of Addictive Diseases 25(1): 43-50, 2006. (33 refs.)
Aim: To evaluate whether effective methadone treatment affects cocaine use. Methods: Four hundred twenty-one consecutive patients admitted to a methadone maintenance clinic in Israel (1993-2002) were prospectively studied. Patients' urine samples were analyzed for cocaine during months 1 and 13. Results: On admission 55(13.1%) of 421 patients had urine positive for cocaine and 366 had negative. Of the 55 cocaine-positive patients, 45(81.8%) stayed in treatment at least one year, as did 267(73%) cocaine-negative. After one year (n = 312) 31 of 45 cocaine users stopped and 25 of 267 started. Methadone dose was highest in 31 patients who stopped. cocaine (176.1 +/- 42.1 mg/day), followed by 14 who did not stop (161.4 +/- 37.5 mg/day), and 25 who started during treatment (122.9 +/- 48.7 mg/day), or 242 who never used cocaine (119.5 +/- 48.4 mg/day) (ANOVA, F = 15.6, p < 0.0005). Conclusions: High methadone dose may reduce cocaine use in patients addicted to both heroin and cocaine.

Differing effects of antipsychotic medications on substance abuse treatment patients with co-occurring psychotic and substance abuse disorders.

Stuyt EB; Sajbel TA; Allen MH. American Journal on Addictions 15(2): 166-173, 2006. (33 refs.)
This retrospective study of patients treated in a ninety-day, inpatient, dual-diagnosis treatment program examined antipsychotic effectiveness in this population using length of stay in treatment and successful program completion as outcome measures. All patients with co-occurring substance dependence and schizophrenia or schizoaffective disorder treated with olanzapine, risperidone, ziprasidone, and typical depot neuroleptics from January 2001 to December 2003 (N = 55) are the subjects of this study. Patients stayed longer in treatment when taking risperidone ( 82 +/- 19 days) or ziprasidone ( 74 +/- 21 days) compared with olanzapine ( 44 +/- 30 days) or typicals ( 47 +/- 36 days). Eighty-eight percent of risperidone patients and 64% of ziprasidone patients successfully completed the program, while only 33% of olanzapine patients and 40% of patients on typicals successfully completed the program. Risperidone and ziprasidone were associated with significantly better program performance than olanzapine or depot typicals in this population. Possible reasons for this difference are discussed.

Illicit drug use and HIV-1 disease progression: A longitudinal study in the era of highly active antiretroviral therapy.

Lucas GM; Griswold M; Gebo KA; Keruly J; Chaisson RE; Moore RD. American Journal of Epidemiology 163(5): 412-420, 2006. (49 refs.)
This study assessed the association between longitudinal patterns of illicit drug use and clinical progression of human immunodeficiency virus (HIV) disease. Confidential computer-based interviews, which addressed illicit drug use and other factors, were completed by HIV-infected participants in Baltimore, Maryland, at 6-month intervals from 1998 onward. To assess this association, the authors used a random-effects model in which clinically defined opportunistic conditions were linked to self-reported periods of drug use, enabling four categories of drug use to be distinguished: nonusers, intermittent users during abstinent periods, intermittent users during active periods, and persistent users. Included in the analysis were 1,851 participants who completed >= 1 survey. For participants who used drugs intermittently over time, the risk of developing new opportunistic conditions during periods of abstinence was similar to that for those who never used drugs (odds ratio = 1.2, 95% confidence interval: 0.9, 1.7). In contrast, compared with that for nonusers, the risk of opportunistic infection was significantly higher for intermittent drug users during periods of active use (odds ratio = 2.2, 95% confidence interval: 1.4, 2.9) and for persistent drug users (odds ratio = 1.9, 95% confidence interval: 1.2, 2.8). Active drug use is temporally linked to HIV disease progression and mortality. Effectively targeting and treating active substance abuse in HIV treatment settings may provide a mechanism to improve clinical outcomes.

Lesson of the week - Opiate toxicity in patients with renal failure. (review).

Conway BR; Fogarty DG; Nelson WE; Doherty CC. British Medical Journal 332(7537): 345-346, 2006. (7 refs.)
Opiates and their metabolites are known to accumulate in renal failure, with increased potential for toxicity, the most serious aspect of which is respiratory failure.1 Despite this knowledge, we continue to see life threatening cases of opiate toxicity in patients with renal failure. Two case examples are presented. One involves a 68 year old woman with type 2 diabetes, angina, and obesity had an uncomplicated below knee amputation. The other is a 63 year old woman with end stage renal failure, type 2 diabetes, and ischaemic heart disease who was found semiconscious in bed. In the discussion it is noted that altered pharmacokinetics of opiates in renal failure may result in the accumulation of the parent compound or an active metabolite. Morphine, for example, is metabolised to morphine-3-glucuronide and morphine-6-glucuronide, both of which are renally excreted. Morphine-6-glucuronide, which is more potent than morphine itself, has a half life of about 50 hours in patients with end stage renal failure compared with 3-5 hours in the presence of normal renal function.3 Pethidine, another commonly prescribed opiate, is converted to the neurotoxic renally excreted metabolite norpethidine. Patients with renal dysfunction are therefore susceptible to opiate toxicity unless doses are reduced or dosing intervals are lengthened appropriately.

Maternal exposure to caffeine and risk of congenital anomalies - A systematic review. (review).

Browne ML. Epidemiology 17(3): 324-331, 2006. (56 refs.)
Background: Caffeine is teratogenic in animal studies when administered at high concentrations. Previous review articles have concluded that maternal caffeine consumption does not influence the risk of congenital anomalies. These reviews were narrative rather than systematic. The objective of the current systematic review is to provide a critical appraisal of epidemiologic evidence. Methods: A search of the MEDLINE/PUBMED database (1966-October 2004) was conducted for all published epidemiologic studies with maternal intake of caffeine as an exposure and major malformations as an outcome. Study characteristics were abstracted, internal validity evaluated, and study findings summarized. Results: Twenty-five papers met the initial criteria for inclusion, of which 18 were subsequently excluded as a result of other limitations. Effect estimates for the remaining 7 studies were generally close to null. Specific subgroup analyses were summarized across studies (associations between coffee and cardiovascular malformations, coffee and oral clefts, and tea and cardiovascular malformations). Summary point estimates ranged from 1.0 to 1.2; the upper limits of all confidence intervals were less than 1.7. Conclusions: There is no evidence to support a teratogenic effect of caffeine in humans. Current epidemiologic evidence is not adequate to assess the possibility of a small change in risk of congenital anomalies resulting from maternal caffeine consumption.

Moderate alcohol use and reduced mortality risk: Systematic error in prospective studies. (review).

Fillmore KM; Kerr WC; Stockwell T; Chikritzhs T; Bostrom A. Addiction Research & Theory 14(2): 101-132, 2006. (99 refs.)
The majority of prospective studies on alcohol use and mortality risk indicates that abstainers are at increased risk of mortality from both all causes and coronary heart disease (CHD). This meta-analysis of 54 published studies tested the extent to which a systematic misclassification error was committed by including as 'abstainers' many people who had reduced or stopped drinking, a phenomenon associated with ageing and ill health. The studies judged to be error free found no significant all-cause or cardiac protection, suggesting that the cardiac protection afforded by alcohol may have been over-estimated. Estimates of mortality from heavier drinking may also be higher than previously estimated.

Lifetime alcohol intake and breast cancer risk.

Terry MB; Zhang FF; Kabat G; Britton JA; Teitelbaum SL; Neugut AI et al. Annals of Epidemiology 16(3): 230-240, 2006. (83 refs.)
PURPOSE: Moderate alcohol intake of one to two drinks per day has been consistently associated with a 30-50% increase in breast cancer. Despite the consistency in the overall association, several important questions remain, including whether the association between alcohol intake and breast cancer risk is affected by the timing of alcohol exposure, modified by other risk factors such as body mass index (BMI), menopausal status, and hormone replacement therapy (HRT), or more pronounced among hormone receptor positive tumors or invasive rather than in situ disease. METHODS: To address these questions, we conducted a large population-based study (1508 cases and 1556 controls) that collected detailed information on alcohol and other exposures throughout the lifecourse. RESULTS: Consumption of 15-30 grams/day (approximately one to two drinks) throughout life was associated with a modest 33% increase in risk (odds ratio [OR] = 1.33, 95% confidence interval (CI) = 1.01-1.74), but heavier consumption (>= 30 grams per day) was not. Risk did not vary with alcohol type (beer, wine, or hard liquor) or by patterns of use, such as recent use, intake prior to age 20 years, or whether use began at an early age. The association with lifetime intake was limited to women with a BMI < 25 (OR = 2.13, 95% CI = 1.29-3.54). Alcohol consumption of approximately one drink per day was associated with estrogen receptor positive tumors among women with a BMI < 25, but not among women BMI >= 25. Also, the elevated OR was observed only among women diagnosed with invasive (OR = 1.56, 95% CI = 1.11-2.18), but not in situ breast tumors. CONCLUSIONS: These data give added support that moderate alcohol consumption over the life course increases breast cancer risk, particularly among women with low BMI and those diagnosed with estrogen receptor positive tumors or with invasive rather than in situ disease. Risk is confined to moderate intake and does not vary with the timing of use, with heavier doses, or with the type of alcohol consumed.

Neurotoxicity of methylenedioxyamphetamines (MDMA; ecstasy) in humans: How strong is the evidence for persistent brain damage? (review).

Gouzoulis-Mayfrank E; Daumann J. Addiction 101(3): 348-361, 2006. (158 refs.)
The popular dance drug ecstasy (3,4-methylenedioxymethamphetamine: MDMA and some analogues) causes selective and persistent neurotoxic damage of central serotonergic neurones in laboratory animals. Serotonin plays a role in numerous functional systems in the central nervous system (CNS). Consequently, various abnormalities including psychiatric, vegetative, neuroendocrine and cognitive disorders could be expected in humans following MDMA-induced neurotoxic brain damage. In recent years, the question of ecstasy-induced neurotoxicity and possible functional sequelae has been addressed in several studies with drug users. The aim of this paper was to review this literature and weigh the strength of the evidence for persistent brain damage in ecstasy users. We used Medline to view all available publications on 'ecstasy' or 'MDMA'. All available studies dealing with ecstasy users entered this analysis. Despite large methodological problems the bulk of evidence suggests residual alterations of serotonergic transmission in MDMA users, although at least partial restitution may occur after long-term abstinence. However, functional sequelae may persist even after longer periods of abstinence. To date, the most consistent findings associate subtle cognitive, particularly memory, impairments with heavy ecstasy use. However, the evidence cannot be considered definite and the issues of possible pre-existing traits or the effects of polydrug use are not resolved. Questions about the neurotoxic effects of ecstasy on the brain remain highly topical in light of its popularity among young people. More longitudinal and prospective studies are clearly needed in order to obtain a better understanding of the possible long-term sequelae of ecstasy use in humans.

Pharmacokinetics, bioavailability and opioid effects of liquid versus tablet buprenorphine.

Compton P; Ling W; Moody D; Chiang N. Drug and Alcohol Dependence 82(1): 25-31, 2006. (12 refs.)
Aims: Two tablet formulations of buprenorphine (a buprenorphine mono-product, subutex(R), and a buprenorphine/naloxone combination product, Suboxone(R)) are available for use in the treatment of opioid addiction; however, the bulk of the clinical studies supporting its approval by the US Food and Drug Administration (FDA) were conducted with a sublingual liquid preparation. To assist the clinician in interpreting the relevant literature in establishing dosing parameters for prescription of tablet buprenorphine, this Study was designed to compare the steady state: (1) pharmacokinetics and bioavailability, and (2) physiological, subjective and objective opiate effects of two 8 mg buprenorphine tablets (16 mg) to those of 1 ml (8 mg/ml) buprenorphine solution based upon early reports Suggesting that the bioavailability of the tablet was approximately 50% of that of the liquid. Design: Randomized, open-label, two-way crossover xtudy. Setting: Inpatient hospitalization for 21 days. Participants: Twenty-four male and females in general good health and meeting DSM-IV criteria for opiate dependence. Intervention: Subjects received one of the two buprenorphine formulations in the first 10-day period, and the other for the second 10-day period with no washout. Measurements: Pharmacokinetic analyses, opiate effects and adverse events. Findings: Drug steady state was reached by Day 7 of each 10-day period, area under the curve for 16 mg (two 8 mg) tablets was higher than the solution. The only non-kinetic statistically significant difference observed between the formulations was in changes in total opioid agonist score. Conclusions: The serum concentration achieved by 16 mg of tablet buprenorphine is higher than that of the 8 mg solution, although differences between physiologic, subjective and objective opioid effects were not noted. The relative bioavailability of tablet versus solution is estimated to be 0.71; thus, with respect to dosing parameters for the tablet, clinicians should consider using less than 16 mg to achieve bioequivalence to the 8 mg solution.

Pseudoephedrine enhances performance in 1500-m runners.

Hodges K; Hancock S; Currell K; Hamilton B; Jeukendrup AE. Medicine and Science in Sports and Exercise 38(2): 329-333, 2006. (20 refs.)
Pseudoephedrine is an over-the-counter drug to relieve nasal and sinus congestion. Although it has been suggested that pseudoephedrine could be a stimulant and ergogenic aid, pseudoephedrine was recently removed front the banned Substance list by the International Olympic Committee and placed on the monitoring program (front January 2004). It was felt that evidence was lacking for an ergogenic effect, although few studies have investigated the effects of pseudoephedrine on exercise performance. This study, therefore, aimed to investigate the effects of pseudoephedrine on 1500-m running performance. Methods: In a double-blind, randomized crossover design, seven male athletes completed two 1500-m running trials on an outdoor track after having completed a familiarization trial. All trials were 7 d apart. After a 12-h overnight fast, subjects reported to the laboratory and received a standardized breakfast (energy approximate to 500 kcal 50% CHO). Subjects were given either 2.5 mg center dot kg(-1) bw pseudoephedrine or 2.5 mg center dot kg(-1) bw maltodextrins (placebo) in gelatin capsules 70 min before the start of the warm-up, which started 20 ruin before the), ran 1500 in all-out. Pre- and postexercise blood samples were collected and analyzed for lactate and glucose concentrations, partial pressure of oxygen (PO2) and carbon dioxide (PCO2). and percent oxygen saturation. Results: Pseudoephedrine significantly decreased time to completion of 1500-m time trials in the present study by 2.1% (from 279.65 +/- 4.36 s with placebo to 273.86 +/- 4.36 s with pseudoephedrine) with no reported side effects. No changes in the measured blood parameters were found, suggesting a central effect of pseudoephedrine rather than a metabolic effect. Conclusion: The finding was that 2.5 bw pseudoephedrine ingested 90 preexercise improves 1500-m running performance.

Stress-induced cocaine craving and hypothalamic-pituitary-adrenal responses are predictive of cocaine relapse outcomes.

Sinha R; Garcia M; Paliwal P; Kreek MJ; Rounsaville BJ. Archives of General Psychiatry 63(3): 324-331, 2006. (53 refs.)
Background: Cocaine dependence is associated with high rates of relapse. Stress and drug cue exposure are known to increase cocaine craving and stress arousal, but the association between these responses and cocaine relapse has not been previously studied. Objective: To examine whether stress-induced and drug cue-induced cocaine craving and hypothalamic-pituitary adrenal axis responses evoked in the laboratory are associated with subsequent cocaine relapse. Design: Prospective study design assessing cocaine relapse and drug use during a 90-day follow-up period after discharge from inpatient treatment and research. Data were analyzed by Cox proportional hazards regression and multiple regression. Setting: Inpatient treatment and research unit in a community mental health center. Patients: Forty-nine treatment-seeking cocaine-dependent individuals. Main Outcome Measures: Time to cocaine relapse, number of days of cocaine use, and amount of cocaine used per occasion in the follow-up phase. Results: Greater stress-induced, but not drug cue induced, cocaine craving was associated with a shorter time to cocaine relapse. Stress-induced corticotropin and cortisol responses predicted higher amounts of cocaine use per occasion in the 90-day follow-up. Conclusions: These results demonstrate that stress-related increases in cocaine craving and hypothalamic-pituitary-adrenal axis responses are each associated with specific cocaine relapse outcomes. The findings support the use of stress-induced drug craving and associated hypothalamic-pituitary-adrenal axis responses to evaluate cocaine relapse propensity. Furthermore, treatments that address stress-induced cocaine craving and hypothalamic-pituitary-adrenal responses could be of benefit in improving relapse outcomes in cocaine dependence.

The cannabis withdrawal syndrome.

Budney AJ; Hughes JR. Current Opinion in Psychiatry 19(3): 233-238, 2006. (51 refs.)
Purpose of review: The demand for treatment for cannabis dependence has grown dramatically. The majority of the people who enter the treatment have difficulty in achieving and maintaining abstinence from cannabis. Understanding the impact of cannabis withdrawal syndrome on quit attempts is of obvious importance. Cannabis, however, has long been considered a 'soft' drug, and many continue to question whether one can truly become dependent on cannabis. Skepticism is typically focused on whether cannabis use can result in 'physiological' dependence or withdrawal, and whether withdrawal is of clinical importance. Recent findings: The neurobiological basis for cannabis withdrawal has been established via discovery of an endogenous cannabinoid system, identification of cannabinoid receptors, and demonstrations of precipitated withdrawal with cannabinoid receptor antagonists. Laboratory studies have established the reliability, validity, and time course of a cannabis withdrawal syndrome and have begun to explore the effect of various medications on such withdrawal. Reports from clinical samples indicate that the syndrome is common among treatment seekers. Summary: A clinically important withdrawal syndrome associated with cannabis dependence has been established. Additional research must determine how cannabis withdrawal affects cessation attempts and the best way to treat its symptoms.