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CORK Bibliography: Abuse Potential

49 citations. January 2007 to present

Prepared: September 2009

Abanades S; Farre M; Barral D; Torrens M; Closas N; Langohr K et al. Relative abuse liability of gamma-hydroxybutyric acid, flunitrazepam, and ethanol in club drug users. Journal of Clinical Psychopharmacology 27(6): 625-638, 2007. (62 refs.)

Objectives: Despite the increasing concern about gamma-hydroxybutyric acid (GHB) toxicity, there are few studies examining the clinical pharmacology of GHB and its abuse potential. To evaluate GHB-induced subjective and physiological effects, its relative abuse liability and its impact on psychomotor performance in club drug users. Materials and Methods: Twelve healthy male recreational users of GHB participated in 5 experimental sessions in the framework of a clinical trial. The study was randomized, double-blind, double-dummy, and crossover. Drug conditions were a single oral dose of GHB (40 or 60 mg/kg), ethanol (0.7 g/kg), flunitrazepam (1.25 mg), and placebo. Study variables included vital signs (blood pressure, heart rate, oral temperature, pupil diameter), psychomotor performance (digit symbol substitution test, balance, Maddox-Wing), subjective effects (a set of 13 visual analogue scales, Addiction Research Center Inventory-49 items, and Evaluation of the Subjective Effects of Substanceances with Potential of Abuse questionnaires), and pharmacokinetics. Results: All active conditions induced positive effects related to their abuse potential. The administration of GHB produced euphoria and pleasurable effects with slightly higher ratings than those observed for flunitrazepam and ethanol. gamma-Hydroxybutyric acid induced a biphasic time profile with an initial stimulantlike effect related to the simultaneous rise of plasma concentrations and a latter sedative effect not related to GHB kinetics. gamma-Hydroxybutyric acid increased blood pressure and pupil diameter. Ethanol induced its prototypical effects, and flunitrazepam produced marked sedation. gamma-Hydroxybutyric acid and flunitrazepam impaired psychomotor performance, digit symbol substitution test, and balance task, whereas ethanol, at the dose tested, induced only mild effects exclusively affecting the balance task. Conclusions: Our results suggest a high abuse liability of GHB and flunitrazepam in club drug users.

Anthierens S; Habraken H; Petrovic M; Christiaens T. The lesser evil? Initiating a benzodiazepine prescription in general practice. Scandinavian Journal of Primary Health Care 25(4): 214-219, 2007. (38 refs.)

Objective. Chronic benzodiazepine (BZD) use is widespread and linked with adverse effects. There is consensus concerning the importance of initiating BZD as a crucial moment. Nevertheless specific research in this field is lacking. This paper addresses the views of GPs on why they start prescribing BZDs to first-time users. Design. Qualitative study with five focus groups analysed using a systematic content analysis. Setting. Regions of Ghent and Brussels in Belgium. Subjects. A total of 35 general practitioners. Main outcome measure. The GPs' perspective on their initiating of BZD prescribing. Results. GPs reported that they are cautious in initiating BZD usage. At the same time, GPs feel overwhelmed by the psychosocial problems of their patients. They show empathy by prescribing. They feel in certain situations there are no other solutions and they experience BZDs as the lesser evil. They admit to resorting to BZDs because of time restraint and lack of alternatives. GPs do not perceive the addictive nature of BZD consumption as a problem with first-time users. GPs do not specifically mention patients' demand as an element for starting. Conclusion. The main concern of GPs is to help the patient. GPs should be aware of the addictive nature of BZD even in low doses and a non-pharmacological approach should be seen as the best first approach. If GPs decide to prescribe a BZD they should make plain to the patient that the medication is only a "temporary" solution with clear agreements with regard to medication withdrawal.

Bailey F; Davies A. The misuse/abuse of antihistamine antiemetic medication (cyclizine) by cancer patients. Palliative Medicine 22(7): 869-871, 2008. (10 refs.)

Cyclizine is an antihistamine, which is frequently used to manage nausea and vomiting in cancer patients. Antihistamines can be drugs of misuse/abuse, and the article describes four cancer patients who developed such problems after receiving parenteral cyclizine within the inpatient unit of a cancer centre. The article also briefly reviews the literature on the misuse/abuse of cyclizine and other antihistamines.

Baruch E; Vernon LF; Hasbun RJ. Intractable nausea caused by Zolpidem withdrawal: A case report. Journal of Addiction Medicine 1(1): 48-50, 2007. (27 refs.)

First launched in France in 1988, zolpidem (Ambien(R)) is a short-acting hypnotic agent. Early studies reported that that the development of physical dependence and tolerance to sedative-hypnotic drugs, such as the depressant and anticonvulsant effects evidenced with benzodiazepines, is not found with zolpidem. Direct to consumer advertising by the manufacturer continues to state that the risk for dependency is low; however, recent publications seem to contradict this. Additionally, adverse drug reactions affecting the central nervous system, gastrointestinal tract, and respiratory system have been reported. Other studies have examined the interactions of selective serotonin reuptake inhibitors and zolpidem as a possible cause of hallucinations. With continued physician marketing efforts touting the safety and efficacy of zolpidem, there is a high likelihood to overlook the risk of dependency and the symptoms related to zolpidem withdrawal. We report a case of a 41-year-old female who developed a dependency to zolpidem, who on her own decided to decrease her dosage, resulting in intractable nausea requiring hospitalization. Reported cases of zolpidem withdrawal have occurred with doses in excess of 160 mg per day, none of these have reported with intractable nausea as the sole symptom. In our reported case, although exceeding recommended dosage withdrawal phenomenon seemed to be severe after withdrawal from a comparatively low dose of zolpidem. Before zolpidem is prescribed, patient education should include warnings about the potential problems associated with dependency and abrupt discontinuation. Education about this common and likely underrecognized clinical phenomenon will help prevent future episodes and minimize the risk of misdiagnosis.

Bieber CM; Fernandez K; Borsook D; Brennan MJ; Butler SF; Jamison RN et al. Retrospective accounts of initial subjective effects of opioids in patients treated for pain who do or do not develop opioid addiction: A pilot case-control study. Experimental and Clinical Psychopharmacology 16(5): 429-434, 2008. (13 refs.)

This pilot case-control study retrospectively assessed between-groups differences in subjective opioid effects in patients treated for the first time with opioids for chronic pain. Cases were individuals in an inpatient substance abuse treatment center for primary prescription opioid addiction whose initial exposure to prescription opioids was reported for chronic pain. Controls had not developed prescription opioid addiction as measured in part by close monitoring on long-term opioid therapy at a pain management center. Twenty subjects in each group completed a battery of measures to capture data related to the individual's first exposure to prescription opioids. The Morphine Benzedrine Group subscale of an adapted 49-item Addiction Center Research Inventory (ARCI), designed to measure euphoria and other drug effects, showed an average score of 8.70 (+/- 4.18) in cases versus 2.55 (+/- 3.36) in controls (p < 0.001), indicating a significantly greater "euphoric" effect of opioids in the cases compared to the controls. Differences in the subjective response to opioids suggest that: (1) a subgroup of patients does develop euphoria when taking opioids for pain, which may be a risk factor for eventual development of prescription opioid addiction; and (2) subjective effects predictive of eventual addiction may include stimulation and other experiences not typically associated with opioids.

Bramness JG; Furu K; Engeland A; Skurtveit S. Carisoprodol use and abuse in Norway. A pharmacoepidemiological study. British Journal of Clinical Pharmacology 64(2): 210-218, 2007. (34 refs.)

What is already known about this subject: Carisoprodol was developed to create a drug with less abuse potential than meprobamate. Case reports have established carisoprodol as a drug of abuse, but no systematic studies have been published about the extent of abuse. What this study adds: A large number of patients used more carisoprodol than recommended. High use of carisoprodol was associated with high use of benzodiazepines and opiates. Compared with other medicinal drugs, carisoprodol showed many prescription database signals of being a potential drug of abuse. Carisoprodol was developed to create a drug with less potential for abuse than meprobamate. However, case reports have established carisoprodol as a drug of abuse. This paper explores the extent of potential abuse of this drug in Norway. The Norwegian Prescription Database contains information on prescription drugs dispensed to individuals in Norway. Patients can be followed over time. High levels of carisoprodol use could indicate use for pleasurable effects or development of tolerance. Concomitant use of other potential drugs of abuse was also studied. We studied drug-seeking behaviour by looking at patients who received carisoprodol from many different pharmacies and doctors or from high-prescribing doctors. Carisoprodol was compared with a series of other medicinal drugs with or without known potential for abuse. Some 53 889 Norwegian women (2.4%) and 29 824 men (1.3%) >= 18 years old received carisoprodol at least once in 2004. Prescribing of carisoprodol was skewed. As many as 32% of the patients received more than 15 defined daily doses (DDDs) of carisoprodol and > 11 000 patients (15%) received >= 75 DDDs in 2004. High users of carisoprodol also received more benzodiazepines and opioids. Few patients used three or more doctors for prescriptions, but carisoprodol-abusing patients more often received their prescription from high-prescribing doctors. Carisoprodol was widely used and the skewedness in use indicated that it is a potential drug of abuse. A large number of patients used more carisoprodol than recommended in the guidelines. The high level of use and abuse of carisoprodol should be of concern in Norway.

Castelli MP. Multi-faceted aspects of gamma-hydroxybutyric acid: A neurotransmitter, therapeutic agent and drug of abuse. (review). Mini Reviews in Medicinal Chemistry 8(12): 1188-1202, 2008. (141 refs.)

Gamma hydroxybutyric acid (GHB), an endogenous constituent of the mammalian brain, acts as i) a neurotransmitter or neuromodulator, ii) a medicine used for the treatment of narcolepsy and alcoholism, and iii) a drug illicitly used for its psychotropic effects. GHB is thought to act as a specific GHB receptor agonist as well as a weak gamma-aminobutyric acid type B (GABA(B)) receptor agonist. Here, I review the in vivo and in vitro pharmacological properties of GHB and its interaction with GHB and GABAB receptors. When exogenously administered, GHB is rapidly absorbed, crosses the blood-brain barrier, penetrates into the brain and exerts a number of pharmacological effects including anxiolysis, sedation/hypnosis and anesthesia. Due to its effects on the central nervous system, GHB has been used for the treatment of narcolepsy and as an anesthetic adjuvant. More recently, a role for GHB in the pharmacotherapy of alcohol dependence has been described. In this review, I also focus on the abuse liability and reinforcing properties of GHB in humans and laboratory animals.

Chen L; Tsong Y. Design and analysis for drug abuse potential studies: Issues and strategies for implementing a crossover design. Drug Information Journal 41(4): 481-489, 2007. (10 refs.)

It is important to conduct a drug abuse potential study for a new drug that may have potential to be abused. The acute dose-effect comparisons of the test, positive control, and placebo treatments are often performed on healthy volunteers with histories of drug abuse in drug abuse clinical trials. Because of large between-subject variability in the endpoint measurements based on self-evaluated responses and the difficulty in recruiting appropriate study subjects; the designs for such studies are typically crossover, with self-control. In this article, design issues and statistical analysis issues are presented. The advantages and disadvantages of currently used study designs are discussed. Some new ideas for improving existing designs are proposed.

Cicero TJ; Lynskey M; Todorov A; Inciardi JA; Surratt HL. Co-morbid pain and psychopathology in males and females admitted to treatment for opioid analgesic abuse. Pain 139(1): 127-135, 2008. (27 refs.)

The purpose of this study was to identify co-morbidity in a national sample (N = 1408) of males and females entering treatment for opioid abuse. Our sample was primarily white, lived in small urban, suburban or rural locations (80%,), and was well-educated. Chronic pain was a symptomatic feature in over 60% of all subjects. Furthermore, 79% of male and 85% of female prescription opioid abusers indicated that their first exposure to an opioid was a legitimate prescription for pain which subsequently led 60-70% to misuse to get high. Our data also indicate that the use of prescription opioids to get high represents the end stage on a continuum of substance abuse, beginning at a very early age. The age of first alcohol use, getting drunk, smoking, use of marijuana, stimulants and other non-opioid prescription or illicit drugs occurred very early (13-19) in prescription opioid misusers/abusers, whose first use of opioids did not occur, on average, until age 22. Finally, most of the sample had sought treatment 3 or more times for substance abuse prior to the treatment admission in which the survey was completed. Physical and mental health were very poor in both male and female prescription opioid abusers, but females were more ill and dysfunctional than males in all physical and particularly emotional domains. Our results suggest that a small number of "at risk" opioid naive pain patients, who might abuse their therapeutically appropriate opioid analgesics, can be identified by assessing pre- and co-morbid substance abuse and significant psychopathology.

Cimolai N. Zopiclone - Is it a pharmacologic agent for abuse? (review). Canadian Family Physician 53: 2124-2129, 2007. (56 refs.)

OBJECTIVE: To determine whether the hypnosedative drug zopiclone could be an agent for abuse. SOURCES OF INFORMATION: Using MEDLINE and PubMed, English-language medical literature was systematically reviewed for reports of direct drug abuse and addiction. A review was also conducted for clinical trials or patient series that discussed issues of addiction or rebound effects. MAIn MESSAGE Evidence of drug abuse and dependency was found in case reports and small patient series. Dependency symptoms of severe rebound, severe anxiety, tremor, palpitations, tachycardia, and seizures were observed in some patients after withdrawal. Abuse occurred more commonly among patients with previous drug abuse or psychiatric illnesses. Many clinical trials have found evidence of rebound insomnia after recommended dosages were stopped, albeit for a minority of patients. Comparative studies of zopiclone and benzodiazepines or other "Z" drugs are conflicting. CONCLUSION Zopiclone has the potential for being an agent of abuse and addiction. While many have suggested that the addictive potential for this and other "Z" drugs is less than for most benzodiazepines, caution should be taken when prescribing this agent for insomnia. ideally, prescriptions should be given for a short period of time and within the recommended dosage guidelines.

Comer SD; Ashworth JB; Foltin RW; Johanson CE; Zacny JP; Walsh SL. The role of human drug self-administration procedures in the development of medications. Drug and Alcohol Dependence 96(1-2): 1-15, 2008. (116 refs.)

The purpose of this review is to illustrate the utility and value of employing human self-administration procedures in medication development, including abuse liability assessments of novel medications and evaluation of potential pharmacotherapies for substance use disorders. Traditionally, human abuse liability testing has relied primarily on subjective reports describing drug action by use of questionnaires; similarly, drug interactions between putative treatment agents and the drugs of abuse have relied on these measures. Subjective reports are highly valued because they provide qualitative and quantitative information about the characteristics of central and peripheral pharmacodynamic effects as well as safety and tolerability. However, self-administration procedures directly examine the behavior of interest-that is, drug taking. The present paper (1) reviews the most commonly used human self-administration procedures, (2) discusses the concordance of subjective reports and self-administration within the context of medications development for substance use disorders, focusing primarily on illustrative examples from development efforts with opioid and cocaine dependence, and (3) explores the utility of applying self-administration procedures to assess the abuse liability of novel compounds, including "abuse-deterrent" formulations (ADFs). The review will focus on opioid and cocaine dependence because a rich database from both clinical laboratory and clinical trial research exists for these two drug classes. The data reviewed suggest that drug-induced changes in self-administration and subjective effects are not always concordant. Therefore, assessment of self-administration in combination with subjective effects provides a more comprehensive picture that may have improved predictive validity for translating to the clinical setting.

Darke S; Kaye S; McKetin R; Duflou J. Major physical and psychological harms of methamphetamine use. (review). Drug and Alcohol Review 27(3): 253-262, 2008. (112 refs.)

Issues. The major physical and psychological health effects of methamphetamine use, and the factors associated with such harms. Approach. Comprehensive review. Key Findings. Physical harms reviewed included toxicity and mortality, cardiovascular/cerebrovascular pathology, dependence and blood-borne virus transmission. Psychological harms include methamphetamine psychosis, depression, suicide, anxiety and violent behaviours. Implications. While high-profile health consequences, such as psychosis, are given prominence in the public debate, the negative sequelae extend far beyond this. This is a drug class that causes serious heart disease, has serious dependence liability and high rates of suicidal behaviours. Conclusion. The current public image of methamphetamine does not portray adequately the extensive, and in many cases insidious, harms caused.

Fu SS; Okuyemi KS; Partin MR; Ahluwalia JS; Nelson DB; Clothier BA et al. Menthol cigarettes and smoking cessation during an aided quit attempt. Nicotine & Tobacco Research 10(3): 457-462, 2008. (20 refs.)

Menthol may make cigarettes more addictive and rates of menthol cigarette smoking are disproportionately higher among Black. However, few studies have examined the association between menthol cigarette smoking and cessation, and the studies to date have produced conflicting findings. The present study examines the effect of menthol cigarette smoking on cessation among a multi-ethnic sample of smokers making a pharmacotherapy-aided quit attempt. We hypothesized that menthol cigarette smoking would be associated with lower smoking abstinence rates and conducted a secondary analysis of data from a multi-site randomized controlled trial of an intervention designed to facilitate repeat tobacco cessation treatment (N=1,343). The intervention consisted of a patient phone call and a computerized provider prompt. The primary outcome for this analysis was 7-day point prevalence smoking abstinence. The average age of the sample was 56 years old. Overall, 25% of the sample smoked menthol cigarettes: 19% of Whites, 62% of Blacks, and 25% of other ethnicity (p<.001). We observed no significant effects for menthol cigarette smoking or ethnicity on smoking abstinence rates. In conclusion, combined with findings from previous research, this study suggests that smoking menthol cigarettes does not decrease smoking cessation among older smokers during a quit attempt aided with pharmacotherapy.

Gable RS. Risk assessment of ritual use of oral dimethyltryptamine (DMT) and harmala alkaloids. (review). Addiction 102(1): 24-34, 2007. (76 refs.)

To extend previous reviews by assessing the acute systemic toxicity and psychological hazards of a dimethyltryptamine and beta-carboline brew (ayahuasca/hoasca) used in religious ceremonies. A systematic literature search, supplemented by interviews with ceremony participants. No laboratory animal models were located that tested the acute toxicity or the abuse potential of ayahuasca. Separate animal studies of the median lethal dose of dimethyltryptamine (DMT) and of several harmala alkaloids indicated that a lethal dose of these substances in humans is probably greater than 20 times the typical ceremonial dose. Adverse health effects may occur from casual use of ayahuasca, particularly when serotonergic substances are used in conjunction. DMT is capable of inducing aversive psychological reactions or transient psychotic episodes that resolve spontaneously in a few hours. There was no evidence that ayahuasca has substantial or persistent abuse potential. Long-term psychological benefits have been documented when ayahuasca is used in a well-established social context. A decoction of DMT and harmala alkaloids used in religious ceremonies has a safety margin comparable to codeine, mescaline or methadone. The dependence potential of oral DMT and the risk of sustained psychological disturbance are minimal.

Gerlach KK; Rohay JM; Gitchell JG; Shiffman S. Use of nicotine replacement therapy among never smokers in the 1999-2006 National Health and Nutrition Examination Surveys. Drug and Alcohol Dependence 98(1/2): 154-158, 2008. (28 refs.)

Nicotine replacement therapies (NRT) have been available without a prescription in the United States since 1996. Given that nicotine, at least as it is delivered through tobacco products, is addictive, we examined whether NRT was being used by individuals who have never smoked cigarettes. Adults (n=18,986) and adolescents (n=9187) who participated in the in-home survey and physical examination components of the 1999-2006 National Health and Nutrition Examination Surveys were assessed for cigarette smoking status, other tobacco use or exposure, and use of NRT. Among the 8415 adults (ages 20 and older) who reported never having smoked 100 cigarettes and who provided a blood sample during their physical exam, 3 (0.08%; 95% CI=0.02-0.28%) reported using NRT within the 5 days prior to being examined. Among the 5510 adolescents (aged 12-19 years) who reported never smoking and who provided a blood sample, 5 (0.12%; 95% CI=0.04%-0.36%) reported using NRT. Analyses of cotinine (a metabolite of nicotine) from their blood samples, along with analysis of their other survey responses regarding additional nicotine exposures suggest that it is unlikely that any of the adults were never smokers using NRT and perhaps 2 adolescents may have been never smokers who used NRT. Based on these assessments, the re-estimated prevalence of NRT use by never smokers would be 0% among adults and 0.05% (95% CI=0.01-0.27%) among adolescents.

Gjerden P; Bramness JG; Slordal L. The use and potential abuse of anticholinergic antiparkinson drugs in Norway: a pharmacoepidemiological study. British Journal of Clinical Pharmacology 67(2): 228-233, 2009. (26 refs.)

What is already known about this subject. Anticholinergic antiparkinson drugs are used to ameliorate extrapyramidal symptoms caused by either Parkinson's disease or antipsychotic drugs, but their use in the treatment of Parkinson's disease is assumed to be in decline. center dot Patients with psychotic conditions have a high prevalence of abuse of drugs, including anticholinergic antiparkinson drugs. What this study adds. Anticholinergic antiparkinson drugs in Norway were primarily prescribed to patients using antipsychotic medication. center dot The risk of abuse of this group of drugs was small, even among patients who probably abused other drugs. The use of anticholinergic antiparkinson drugs is assumed to have shifted from the therapy of Parkinson's disease to the amelioration of extrapyramidal adverse effects induced by antipsychotic drugs. There is a considerable body of data suggesting that anticholinergic antiparkinson drugs have a potential for abuse. The aim was to investigate the use and potential abuse of this class of drugs in Norway. Data were drawn from the Norwegian Prescription Database on sales to a total of 73 964 patients in 2004 of biperiden and orphenadrine, and use in patients with Parkinson's disease or in patients who were also prescribed antipsychotic agents. Possible abuse of these drugs was assessed by the level of use, skewedness of use, indications of drug-seeking behaviour and concomitant use of benzodiazepine tranquillizers, a group of prescription drugs with a recognized potential for abuse. Anticholinergic antiparkinson drugs were prescribed to 4.5% of all outpatients who used antipsychotic drugs. This outnumbered sales to patients with Parkinson's disease by > 20 to 1. We found indications of abuse of benzodiazepine tranquillizers among patients using antipsychotics, but there were no clear indications of abuse of anticholinergics, even among patients who were strongly suspected of abuse of benzodiazepines. Anticholinergic antiparkinson drugs were used primarily by patients with psychotic illnesses. These patients have a very high prevalence of legal and illegal drug abuse, but the risk of abuse of anticholinergic antiparkinson drugs seemed small.

Greenwald MK. Behavioral economic analysis of drug preference using multiple choice procedure data. Drug and Alcohol Dependence 93(1/2): 103-110, 2008. (31 refs.)

The multiple choice procedure has been used to evaluate preference for psychoactive drugs, relative to money amounts (price), in human subjects. The present re-analysis shows that MCP data are compatible with behavioral economic analysis of drug choices. Demand curves were constructed from studies with intravenous fentanyl, intramuscular hydromorphone and oral methadone in opioid-dependent individuals; oral d-amphetamine, oral MDMA alone and during fluoxetine treatment, and smoked marijuana alone or following naltrexone pretreatment in recreational drug users. For each participant and dose, the MCP crossover point was converted into unit price (UP) by dividing the money value ($) by the drug dose (mg/70 kg). At the crossover value, the dose ceases to function as a reinforcer, so "0" was entered for this and higher UPs to reflect lack of drug choice. At lower UPs, the dose functions as a reinforcer and "1" was entered to reflect drug choice. Data for UP vs. average percent choice were plotted in log-log space to generate demand functions. Rank of order of opioid inelasticity (slope of non-linear regression) was: fentanyl > hydromorphone (continuing heroin users) > methadone > hydromorphone (heroin abstainers). Rank order of psychostimulant inelasticity was d-amphetamine > MDMA > MDMA + fluoxetine. Smoked marijuana was more inelastic with high-dose naltrexone. These findings show this method translates individuals' drug preferences into estimates of population demand, which has the potential to yield insights into pharmacotherapy efficacy, abuse liability assessment, and individual differences in susceptibility to drug abuse.

Gugger JJ; Cassagnol M. Low-dose quetiapine is not a benign sedative-hypnotic agent. (letter). American Journal on Addictions 17(5): 454-455, 2008. (6 refs.)

Hillemacher T; Bleich S; Demling J; Kornhuber J. Ketamine for the treatment of depression: What about the addictive potential? Australian and New Zealand Journal of Psychiatry 41(9): 772-773, 2007. (5 refs.)

Jasinski DR; Faries DE; Moore RJ; Schuh LM; Allen AJ. Abuse liability assessment of atomoxetine in a drug-abusing population. Drug and Alcohol Dependence 95(1/2): 140-146, 2008. (34 refs.)

Background: Atomoxetine is a non-amphetamine medication approved to treat ADHD in children, adolescents, and adults. Previous studies demonstrated low abuse potential for atomoxetine in recreational drug users. This study assessed the abuse potential of atomoxetine in stimulant-preferring drug abusers compared to methylphenidate and phentermine as positive controls and desipramine and placebo as negative controls. Methods: Forty male and female, 32-53 years old stimulant-preferring drug abusers completed this balanced Latin-square designed study. Subjects received acute, double-blind doses of placebo, desipramine (100 and 200mg), methylphenidate (90mg), phentermine (60mg), and atornoxetine (45, 90, and 180 mg). Subjective and physiological effects were collected for 24 It following each drug treatment. Results: Methylphenidate and phentermine were liked significantly more than placebo, atomoxetine, or desipramine. No atomoxetine dose was liked significantly more than placebo and liking scores for atomoxetine were similar to, or significantly lower than, desipramine, as assessed by the Drug Rating Questionnaire-Subject. While atomoxetine 45 and 180 mg did not significantly change any Addiction Research Center Inventory (ARCI) scores, atomoxetine 90 mg significantly increased A and BG stimulant scores of the ARCI and both methylphenidate and phentermine produced greater A and BG increases than any atomoxetine dose and also increased MBG (euphoria) scores relative to placebo. Conclusions: Atomoxetine has significantly less abuse liability than methylphenidate or phentermine and no greater abuse liability than desiprarnme.

Jasinski DR; Krishnan S. Abuse liability and safety of oral lisdexamfetamine dimesylate in individuals with a history of stimulant abuse. Journal of Psychopharmacology 23(4): 419-427, 2009

Lisdexamfetamine dimesylate (LDX) is the first prodrug stimulant and is indicated for the treatment of attention-deficit/hyperactivity disorder. A single-centre, double-blind, randomised, placebo-controlled, 6-period crossover study evaluated the abuse potential of single oral doses of 50, 100 (equivalent to 40 mg d-amphetamine), and 150 mg LDX, 40 mg d-amphetamine and 200 mg diethylpropion in 36 individuals with a history of stimulant abuse. On the primary abuse liability measure, maximum change of the Drug Rating Questionnaire-Subject Liking Scale compared with placebo, d-amphetamine and diethylpropion showed significant differences of 4.5 and 4.0 units, respectively (P < 0.001 for both vs placebo). LDX, administered at 50, 100 and 150 mg, showed nonsignificant differences of 2.0 and 2.1 units, respectively, at the two lower doses but a significant (P < 0.001 vs placebo) difference of 6.1 units at the highest dose. Subjects significantly favoured d-amphetamine 40 mg versus LDX 100 mg (2.4 units difference; P < 0.05). There was no significant difference in liking scores between d-amphetamine 40 mg and LDX 150 mg. Drug Rating Questionnaire-Subject Feel-Drug-Effect score was significantly lower for 100 mg LDX than for 40 mg d-amphetamine. There were no statistically significant differences between LDX and diethylpropion hydrochloride, a Schedule IV amphetamine-like stimulant, on abuse-related liking scores. Cardiovascular responses of LDX and d-amphetamine were similar at equivalent doses. In conclusion, at an equivalent amount of amphetamine base taken orally, LDX 100 mg had attenuated responses on measures of abuse liability compared with immediate-release d-amphetamine 40 mg. Abuse-related liking scores of LDX at a dose corresponding to a 50% higher amphetamine base (LDX 150 mg) were similar to d-amphetamine 40 mg.

Jasinski DR; Krishnan S. Human pharmacology of intravenous lisdexamfetamine dimesylate: Abuse liability in adult stimulant abusers. Journal of Psychopharmacology 23(4): 410-418, 2009

The objective of this study is to determine the safety, tolerability and abuse liability of single intravenous (i.v.) doses of lisdexamfetamine dimesylate (LDX) and immediate-release d-amphetamine sulphate in adult stimulant abusers compared with placebo. Adult substance abusers were enrolled in this phase I, randomized, single-centre, double-blind study. An initial cohort of three subjects was enrolled to assess safety followed by a primary cohort that consisted of nine subjects. Single i.v. doses of LDX (25 or 50 mg), immediate-release d-amphetamine sulphate (10 or 20 mg) or placebo were administered at a minimum of 48-h intervals in a single-dose, three-way crossover design. 20 mg of d-amphetamine showed significantly increased abuse-related liking scores compared with placebo (P < 0.05), whereas the liking effects of 50 mg LDX did not significantly differ from placebo. The mean C-max of d-amphetamine was 38.9 +/- 8.1 and 105 +/- 91.4 ng/ml after the administration of 50 mg LDX and 20 mg d-amphetamine respectively. The mean T-max of d-amphetamine was 2.51 h after the administration of 50 mg LDX and 0.82 h after the administration of 20 mg d-amphetamine. LDX was well tolerated in this population. In contrast to d-amphetamine, LDX administered intravenously did not produce significant subjective abuse-related liking scores at assessed doses.

Keane H. Pleasure and discipline in the uses of Ritalin. International Journal of Drug Policy 19(5, Special Issue): 401-409, 2008. (56 refs.)

Background: The stimulant drug methylphenidate, otherwise known as Ritalin, is the mainstay of treatment for Attention Deficit Hyperactivity Disorder and is the most common psychotropic medication prescribed to children. Whilst psychiatric discourse presents it as a safe and effective treatment, critics point out its similarity to drugs like cocaine and describe it as "legalised speed". This article examines the ambivalent identity of Ritalin as both benign medicine and dangerous drug. Methods: This paper draws on and analyses existing medical and critical literature on Ritalin, as well psychopharmacological literature on pleasure and drug use. Results: Anxiety about the nature and use of Ritalin reflects tensions within medical and drug science about the therapeutic use of psychoactive drugs. Pleasure is central to this anxiety, as medically authorised use of drugs must not be contaminated by the uncontrolled bodily pleasures of illicit drug use. This is particularly the case for a drug like Ritalin which is used specifically to improve self-discipline and self-regulation. But the association of Ritalin with discipline rather than pleasure is complicated by pharmacological and behavioural evidence of its effects on neural reward systems and its capacities as a positive reinforcer. Conclusion: Ritalin is likely to maintain its ambivalent identity in medical, legal and popular discourses, despite lack of evidence of widespread abuse and addiction. The question of the correct use of Ritalin remains ultimately uncertain because of the heterogeneous and ambiguous nature of the scientific and medical discourses on psychoactive drugs.

Kream RM; Stefano GB. Homeopathic ethanol. Medical Science Monitor 14(9): SC11-SC13, 2008. (42 refs.)

Ethanol has had a long and deep association with the historical development of world culture. Ostensibly, its consumption has both short and long term positive and negative effects, based on moderate or excessive intake, respectively. The predominant thrust of empirical research, however, into the multiple biological effects of ethanol has led to its negative designation as a major addictive substance. Multiple lines of research have elucidated functional interactions of ethanol in opioid modulation of dopaminergic transmission in CNS reward systems. Parallel, recent work has demonstrated that animal cells have the ability to effect de novo synthesis of chemically authentic morphine from dopamine (DA) and DA-related aromatic precursor molecules. Interestingly, we have observed that sub-threshold concentrations of ethanol alter cellular distributions of endogenously expressed morphine. Reciprocal autocrine/paracrine modulatory effects, low concentrations of morphine in concert with ethanol also suggest the potential for endogenous expression and action of homeopathic concentrations of ethanol within discrete cellular microdomains. Perturbation of this subtle regulatory relationship by exogenous intake of ethanol may shed light on the biochemical and molecular bases of reward and addictive states.

Kumar R. Approved and investigational uses of modafinil: An evidence-based review. (review). Drugs 68(13): 1803-1839, 2008. (164 refs.)

Modafinil is a wake-promoting agent that is pharmacologically different from other stimulants. It has been investigated in healthy volunteers, and in individuals with clinical disorders associated with excessive sleepiness, fatigue, impaired cognition and other symptoms. This review examines the use of modafinil in clinical practice based on the results of randomized, double-blind, placebo-controlled clinical trials available in the English language in the MEDLINE database. In sleep-deprived individuals, modafinil improves mood, fatigue, sleepiness and cognition to a similar extent as caffeine but has a longer duration of action. Evidence for improved cognition in non-sleep-deprived healthy volunteers is controversial. Modafinil improves excessive sleepiness and illness severity in all three disorders for which it has been approved by the US FDA, i.e. narcolepsy, shift-work sleep disorder and obstructive sleep apnoea with residual excessive sleepiness despite optimal use of continuous positive airway pressure (CPAP). However, its effects on safety on the job and on morbidities associated with these disorders have not been ascertained. Continued use of CPAP in obstructive sleep apnoea is essential. Modafinil does not benefit cataplexy. In very small, short-term trials, modafinil improved excessive sleepiness in patients with myotonic dystrophy. It was efficacious in fairly large studies of attention deficit hyperactivity disorder (ADHD) in children and adolescents, and was as efficacious as methylphenidate in a small trial, but has not been approved by the FDA, in part because of its serious dermatological toxicity. In a trial of 21 non-concurrent subjects, with 2-week treatment periods, modafinil was as effective as dexamfetamine in adult ADHD.Modafinil was helpful for depressive symptoms in bipolar disorder in a trial that excluded patients with stimulant-induced mania. A single dose of modafinil may hasten recovery from general anaesthesia after day surgery. A single dose of modafinil improved the ability of emergency room physicians to attend didactic lectures after a night shift, but did not improve their ability to drive home and caused sleep disturbances subsequently. Modafinil had a substantial placebo effect on outcomes such as fatigue, excessive sleepiness and depression in patients with traumatic brain injury, major depressive disorder, schizophrenia, post-polio fatigue and multiple sclerosis; however, it did not provide any benefit greater than placebo. Trials of modafinil for excessive sleepiness in Parkinson's disease, cocaine addiction and cognition in chronic fatigue syndrome provided inconsistent results; all studies had extremely small sample sizes. Modafinil cannot be recommended for these conditions until definitive data become available. Modafinil induces and inhibits several cytochrome P450 isoenzymes and has the potential for interacting with drugs from all classes. The modafinil dose should be reduced in the elderly and in patients with hepatic disease. Caution is needed in patients with severe renal insufficiency because of substantial increases in levels of modafinil acid. Common adverse events with modafinil include insomnia, headache, nausea, nervousness and hypertension. Decreased appetite, weight loss and serious dermatological have been reported with greater frequency in children and adolescents, probably due to the higher doses (based on bodyweight) used. Modafinil may have some abuse/addictive potential although no cases have been reported to date.

MacKillop J; Murphy JG; Ray LA; Eisenberg DTA; Lisman SA; Lum JK et al. Further validation of a cigarette purchase task for assessing the relative reinforcing efficacy of nicotine in college smokers. Experimental and Clinical Psychopharmacology 16(1): 57-65, 2008. (30 refs.)

The authors sought to further validate a cigarette purchase task (CPT), a self-report analogue of a progressive-ratio operant schedule, for the assessment of the relative reinforcing efficacy (RRE) of nicotine in smokers. The measure was assessed in terms of its correspondence to typically observed operant behavior, convergent validity, and divergent validity. Participants were 33 individuals (58% male, age M = 19.30 years) who smoked at least weekly (M = 5.31 cigarettes/day) and underwent a single assessment session. Data from the CPT exhibited the predicted inverse relationship between consumption and price, the predicted relationship between consumption and expenditure, and a heterogeneous pattern of interrelationships among the indices of reinforcement. In addition, 2 indices from the measure, intensity of demand and maximum expenditure for cigarettes, exhibited robust convergent and divergent validity. Although this is an incipient research area and the current study used a relatively small sample, these findings support the validity of a CPT as a time- and cost-efficient method for assessing nicotine reinforcement. Theoretical implications of the findings, limitations, and future directions are also discussed.

Maremmani I; Pacini M. Use of sodium gamma-hydroxybutyrate (GHB) in alcoholic heroin addicts and polydrug-abusers. (review). Heroin Addiction and Related Clinical Problems 9(1): 55-76, 2007

Sodium gamma-hydroxybutyrate (GHB) in one of the most effective options available for the treatment of hard-core alcoholism in maintenance programmes that aim to achieve relapse prevention and rehabilitation. Polysubstance abuse and multiple addiction have become quite common in alcoholic youths and former heroin addicts receiving inadequate or no specific treatment. In approaching these categories, GHB is usually neglected, on the basis of the idea that its abuse potential must be amplified in abuse-prone individuals. However, the normalizing effects of anticraving treatment on the behaviour of heroin addicts may make GHB a suitable remedy for the heroin-alcohol polyabuse picture. The same cannot be said of cocaine abusers, due to the lack of anticraving treatments possessing major, reliable effectiveness. After reviewing the data in the literature on the use of GHB in alcoholics and other kinds of abusers, we describe 13 cases of alcohol-abusing heroin addicts, in which GHB proved to possess some effectiveness, even if there were major limitations regarding compliance and completeness of response.

Martins SS; Copersino ML; Soderstrom CA; Smith GS; Dischinger PC; McDuff DR et al. Risk of psychoactive substance dependence among substance users in a trauma inpatient population. Journal of Addictive Diseases 26(1): 71-77, 2007. (27 refs.)

One measure of a substance's addictive risk is the proportion of users who become dependent. This study evaluates the lifetime and current risk of substance dependence among lifetime substance users among trauma inpatients and provides a relative ranking of addictive risk among the substances. Data on use of 8 substance groups (alcohol, opiates, cannabis, cocaine, other stimulants, sedative-hypnotics, hallucinogens, other drugs) were obtained by interview (Structured Clinical Interview for the DSM-III-R) from 1,118 adult trauma inpatients. Prevalence of lifetime dependence among lifetime users ranged from 80.7% for opiates and 70.9% for cocaine to 33.3% for hallucinogens and 26.6% for sedative-hypnotics. The rank order of addictive risk was similar to that found in the general population. Trauma inpatients had a higher absolute addictive risk than the general population, comparable to the risk found in patients in treatment for substance use disorders, suggesting the importance of screening trauma inpatients for substance dependence.

McColl SL; Burstein AH; Reeves KR; Billing CB; Stolar M; Sellers EM. Human abuse liability of the smoking cessation drug varenicline in smokers and nonsmokers. Clinical Pharmacology and Therapeutics 83(4): 607-614, 2008. (39 refs.)

Varenicline is an alpha(4)beta(2) nicotinic acetylcholine receptor partial agonist developed as an aid for smoking cessation. This study evaluated varenicline's potential for abuse by smokers (n = 23) and nonsmokers (n = 22). The study used a randomized, double-blind, placebo-controlled, double-dummy crossover design with five treatment periods: 15 and 30 mg amphetamine, 1 and 3 mg varenicline, and placebo. Following each treatment, the participants were assessed on aspects relating to potential abuse of the drug (e. g., drug liking, drug high, and drug monetary value). The positive effects measured for 3 mg varenicline were similar to those for the placebo, and significantly lower than those for amphetamine in both smokers and nonsmokers. unpleasant effects were reported for 3 mg varenicline in both participant groups. For 1 mg varenicline, the overall patterns were similar, with the exception that the nonsmokers group showed some small positive effects balanced by some negative effects when compared with the effects of placebo. These findings lead to the conclusion that varenicline is unlikely to be abused.

Owens C; Pugmire B; Salness T; Culbertson V; Force R; Cady P et al. Abuse potential of carisoprodol: A retrospective review of Idaho medicaid pharmacy and medical claims data. Clinical Therapeutics 29(10): 2222-2225, 2007. (17 refs.)

Background: Carisoprodol is a muscle relaxant indicated as adjunctive therapy in acute, painful musculoskeletal conditions. Case reports of drug-seeking behavior and utilization of carisoprodol in combination with opioids have suggested abuse potential. Objectives: We undertook a retrospective review of claims data to identify and characterize potential indicators of abuse in long-term users of carisoprodol and to determine any continued use of the drug by former long-term users following prior authorization implementation. Methods: The Idaho Medicaid pharmacy and medical claims database was queried from January 1 to December 31, 2005, to identify long-term users of muscle relaxants. Use of concomitant opiolds and coded diagnoses relating to past drug abuse were analyzed,zed and compared between patients who used carisoprodol and patients who used other muscle relaxants. Data from 11 of 30 surveys mailed to pharmacies filling prescriptions for long-term users of carisoprodol were also collected to determine the frequency of self-pay-continued use after Medicaid coverage of the drug was discontinued. Results: Long-term users of carisoprodol (n = 340) and other skeletal muscle relaxants (SMRs) (n = 453) were identified from among 130,000 individuals in the Idaho Medicaid pharmacy and medical claims database in calendar year 2005. Patients in both groups were similar in terms of mean age (-47 years) and sex (71.5% female). Patients using carisoprodol used concomitant oploids more frequently (81.5% vs 59.8%; P < 0.01), more commonly had past diagnoses indicating other drug abuse (34.1% vs 21.4%; P < 0.01), and in 80% of reported cases, continued to pay out of pocket for carlsoprodol when third-party coverage was discontinued. Taken together, these findings are consistent with published case reports suggesting the abuse potential of carlsoprodol. Conclusions: The results from this review suggest that, compared with long-term users of other SMRs, carisoprodol patients utilized concomitant opioids more frequently and concomitant NSAIDs less frequently, more commonly had past diagnoses indicating other drug dependence or abuse, and continued to pay out of pocket for carisoprodol when third-party coverage was discontinued. While none of these issues alone may be direct indicators of abuse, collectively they suggest that patients who used carisoprodol long term displayed abuse potential characteristics more frequently than long-term users of other agents.

Palmer RHC; Young SE; Hopfer CJ; Corley RP; Stallings MC; Crowley TJ et al. Developmental epidemiology of drug use and abuse in adolescence and young adulthood: Evidence of generalized risk. Drug and Alcohol Dependence 102(1/3): 78-87, 2009. (63 refs.)

Past studies highlight a narrowing gender gap and the existence of a shared etiology across substances of abuse; however, few have tested developmental models using longitudinal data. We present data on developmental trends of alcohol, tobacco, and marijuana use, abuse and dependence assessed during adolescence and young adulthood in a community-based Colorado twin sample of 1733 respondents through self-report questionnaires and structured psychiatric interviews. Additionally, we report on the rates of multiple substance use and disorders at each developmental stage, and the likelihood of a substance use disorder (SUD: i.e., abuse or dependence) diagnosis in Young adulthood based on adolescent drug involvement. Most notably, we evaluate whether the pattern of multiple substance use and disorders and likelihood ratios across substances support a model of generalized risk. Lastly, we evaluate whether the ranked magnitudes of substance-specific risk match the addiction liability ranking. Substance use and SUDs are developmental phenomena, which increase from adolescence to Young adulthood with few and inconsistent gender differences. Adolescents and young adults are not specialized users, but rather tend to use or abuse multiple substances increasingly with age. Risk analyses indicated that progression toward a SUD for any substance was increased with prior involvement with any of the three substances during adolescence. Despite the high prevalence of alcohol use, tobacco posed the greatest substance-specific risk for developing subsequent problems. Our data also confirm either a generalized risk or correlated risk factors for early onset substance use and subsequent development of SUDs.

Parasrampuria DA; Schoedel KA; Schuller R; Silber SA; Ciccone PE; Gu J et al. Do formulation differences alter abuse liability of methylphenidate? - A placebo-controlled, randomized, double-blind, crossover study in recreational drug users. Journal of Clinical Psychopharmacology 27(5): 459-467, 2007. (35 refs.)

The primary objective of this study was to determine if the abuse liability of methylphenidate is governed by formulation differences that affect rates of drug delivery. In this double-blind, placebo-controlled, randomized, crossover study, subjects with a history of recreational drug use received single oral doses of placebo, 60 mg of immediate-release methylphenidate (IR) and 108 mg of extended-release methylphenidate (osmotic release oral system [OROS]). Over 24 hours after dosing, blood was collected to determine plasma concentrations of methylphenidate, and subjects completed subjective assessments of abuse liability (Addiction Research Center Inventory, Drug Rating Questionnaire-Subject, and Subjective Drug Value). The abuse-related subjective effects of IR and OROS methylphenidate were statistically significantly different from placebo, confirming the overall validity of the study. Although a higher dose of OROS methylphenidate was used compared with IR methylphenidate (108 mg vs 60 mg), subjective effects were consistently lower for OROS compared with IR methylphenidate (statistically significant for 3 of 6 measures of positive effects), particularly at early time points. In general, pharmacokinetic-pharmacodynamic parameters were correlated from a poor to modest degree, with greater correlations observed for IR methylphenidate. In addition,, a post hoc "qualification" method was developed, which demonstrated that pharmacological qualification might improve the assessment of subjective effects. Although requiring epidemiological confirmation, the results suggest that OROS methylphenidate, with its characteristic slow ascending plasma concentration profile, may have lower abuse potential. This conclusion is reflected by lower subjective responses during early hours as compared with the IR formulation with its rapid drug delivery and accompanying greater subjective effects.

Reeves RR. Abuse of olanzapine by substance abusers. Journal of Psychoactive Drugs 39(3): 297-299, 2007. (18 refs.)

Olanzapine has been used for over a decade for treatment of schizophrenia and bipolar disorder. The drug may have sedative properties for some patients, especially in large doses. The case reported here involves a 25-year-old male who abused olanzapine, both by itself and in combination with other drugs. Also described are the patient's reports of abuse of olanzapine by several of his acquaintances. The potential for abuse of olanzapine by substance abusers is discussed.

Reeves RR; Brister JC. Additional evidence of the abuse potential of quetiapine. Southern Medical Journal 100(8): 834-836, 2007. (8 refs.)

Quetiapine is an atypical antipsychotic agent approved by the FDA for the treatment of schizophrenia, acute mania, and bipolar depression. Recently, reports of medication abuse, particularly intranasal and IV abuse, have been described. Three cases of oral misuse of quetiapine are presented and clinical implications are discussed. Clinicians should exercise caution when prescribing quetiapine to patients at risk for substance abuse.

Reeves RR; Hammer JS; Pendarvis RO. Is the frequency of carisoprodol withdrawal syndrome increasing? Pharmacotherapy 27(10): 1462-1466, 2007. (31 refs.)

Carisoprodol is a commonly used centrally acting muscle relaxant. A number of case reports have suggested that the drug may have abuse potential, presumably because it is metabolized to the anxiolytic drug, meprobamate, which is a controlled substance at the federal level. Two recent case reports described symptoms of withdrawal after the cessation of carisoprodol. We present two additional cases that support the concept of a withdrawal syndrome with this drug. Symptoms of carisoprodol withdrawal include anxiety, tremulousness, insomnia, jitteriness, muscle twitching, and hallucinations. These symptoms are most likely caused by withdrawal from the meprobarnate that accumulates after large amounts of carisoprodol are ingested. Although carisoprodol is not a controlled substance at the federal level, clinicians should be aware of its significant potential for abuse.

Rosenblum A; Marsch LA; Joseph H; Portenoy RK. Opioids and the treatment of chronic pain: Controversies, current status, and future directions. (review). Experimental and Clinical Psychopharmacology 16(5): 405-416, 2008. (147 refs.)

Opioids have been regarded for millennia as among the most effective drugs for the treatment of pain. Their use in the management of acute severe pain and chronic pain related to advanced medical illness is considered the standard of care in most of the world. In contrast, the long-term administration of an opioid for the treatment of chronic noncancer pain continues to be controversial. Concerns related to effectiveness, safety, and abuse liability have evolved over decades, sometimes driving a more restrictive perspective and sometimes leading to a greater willingness to endorse this treatment. The past several decades in the United States have been characterized by attitudes that have shifted repeatedly in response to clinical and epidemiological observations, and events in the legal and regulatory communities. The interface between the legitimate medical use of opioids to provide analgesia and the phenomena associated with abuse and addiction continues to challenge the clinical community, leading to uncertainly about the appropriate role of these drugs in the treatment of pain. This narrative review briefly describes the neurobiology of opioids and then focuses on the complex issues at this interface between analgesia and abuse, including terminology, clinical challenges, and the potential for new agents, such as buprenorphine, to influence practice.

Schoedel KA; Sellers EM. Assessing abuse liability during drug development: Changing standards and expectations. Clinical Pharmacology and Therapeutics 83(4): 622-626, 2008. (24 refs.)

As public health concerns have changed, regulatory expectations for assessing abuse liability of new central nervous system (CNS) drugs have increased. All CNS-active drugs with any properties indicating stimulant, depressant, hallucinogenic, or mood-elevating effects will require an evaluation of abuse liability. Abuse liability assessment involves the collection, analysis, and interpretation of data on chemistry and tampering, animal behavioral pharmacology, clinical trial adverse events (AEs), diversion and overdose, and potentially reinforcing (subjective) effects in recreational drug users.

Sigmon SC. Investigating the pharmacological and nonpharmacological factors that modulate drug reinforcement. (review). Experimental and Clinical Psychopharmacology 15(1): 1-20, 2007. (113 refs.)

Drug use is driven by principles of reinforcement and is sensitive to influences in the environmental context in which it occurs. Although a wide range of factors has been shown to directly influence the reinforcing effects of commonly abused drugs, 2 general types include pharmacological and nonpharmacological factors. Both can assert a powerful impact on a drug's reinforcing effects and, therefore, the degree to which a particular drug comes to be used and abused. This invited review seeks to briefly describe some of the current psychopharmacology research on the interactions between these factors and drug abuse. Several pharmacological influences on drug use will be discussed, including the interactions between psychomotor stimulants and recent advances in the development of pharmacotherapies for opioid abuse. With regard to nonpharmacological factors, there is a large bode of research demonstrating that nondrug reinforcers can exert a powerful influence oil the reinforcing effects of commonly abused drugs. More specifically, identifying alternative nondrug sources of reinforcement can, if made available contingent on drug abstinence, produce robust decreases in drug self-administration. Presented here is a very brief review of some recent scientific efforts to develop and extend behavioral interventions targeting drug use across a wide range of clinical populations. In summary, understanding the interactions among the variables present in the context of drug use is critical to understanding risk factors for substance use disorders as well as developing efficacious treatments for drug dependence.

Simojoki K; Vorma H; Alho H. A retrospective evaluation of patients switched from buprenorphine (subutex) to the buprenorphine/naloxone combination (suboxone). Substance Abuse Treatment, Prevention and Policy 3: e-article 16, 2008. (6 refs.)

Background: In Finland, buprenorphine (Subutex) is the most abused opioid. In order to curb this problem, many treatment centres transferred ("forced transfer") their buprenorphine patients to the buprenorphine plus naloxone (Suboxone) combination product in late 2003. Methods: Data from a retrospective study involving five different treatment centers, examining the effects of switching patients to Suboxone, were gathered from 64 opioid-dependent patients who had undergone the medication transfer. Results: Most patients (90.6%) switched to Suboxone at the same dose of buprenorphine that they had been receiving as Subutex (average 22 mg). The majority of these patients (71.9%) were maintained at the same dose of Suboxone throughout the 4-week study period. During the first 4 weeks, 50% of the patients reported adverse events and at the four month time point, 26.6% reported adverse events. However, due to adverse events one patient only discontinued treatment with Suboxone during the 4-week study period, and five during the four month follow-up period. Of the 26 patients in the follow-up period, Suboxone was misused intravenously once each by 4 patients and twice by 1 patient. These 5 patients all reported that injecting Suboxone was like injecting "nothing" with any euphoria, or that it was a bad experience. Conclusion: We conclude that when patients are transferred from high doses (> 22 mg) of buprenorphine to the combination product, dose adjustments may be necessary especially in the later phase of the treatment. We recommend that a transfer from Subutex to Suboxone should be carefully discussed and planned in advance with the patients and after the transfer adverse events should be regularly monitored. With regard of buprenorphine IV abuse, the combination product seems to have a less abuse potential than buprenorphine alone.

Singhal A; Tripathi BM; Pal HR; Jena R; Jain R. Subjective effects of additional doses of buprenorphine in patients on buprenorphine maintenance. Addictive Behaviors 32(2): 320-331, 2007. (28 refs.)

Objectives: Buprenorphine has considerable abuse potential. Patients who are maintained on buprenorphine (for opioid dependence) further use additional doses besides its maintenance dose. Subjective effects of the additional doses of buprenorphine in patients on buprenorphine maintenance patients is focused in this study. Methods: Nineteen subjects who were maintained on buprenorphine 4mg, s/l per day for at least I month were admitted and given three additional doses of buprenorphine 2mg, s/l at the interval of 2h each and subjective effects were assessed with the help of standard tools after 2h of each dose and the next day also. Drug was given in a cumulative dose design in the inpatient unit of a de-addiction centre. Results: Dysphoria and sleepiness increased while euphoria and drug liking decreased with additional doses of buprenorphine. These changes were statistically significant and were highest at maximum cumulative dose of 10mg. Conclusion: Results suggest that abuse liability of buprenorphine in these subjects is low in higher doses. However, these findings need to be replicated in this group of patients to make a comment on clinical implication.

Stoops WW; Vansickel AR; Lile JA; Rush CR. Acute d-amphetamine pretreatment does not alter stimulant self-administration in humans. Pharmacology, Biochemistry and Behavior 87(1): 20-29, 2007. (50 refs.)

Recent clinical research indicates that d-amphetamine is effective in treating cocaine and methamphetamine dependence. There is concern, however, with the use of d-amphetamine as a pharmacotherapy because acute administration of d-amphetamine decreases inhibition in cocaine-using individuals and may increase drug-taking behavior. The purpose of the present experiment was to determine whether acute d-amphetamine pretreatment would alter the reinforcing, subject-rated, and cardiovascular effects of d-amphetamine. To this end, 7 human volunteers first sampled doses of oral d-amphetamine (0, 8, and 16 mg). These doses engender moderate drug taking and were selected to avoid a ceiling or floor effect. Volunteers were then allowed to self-administer these sampled doses using a modified progressive-ratio procedure in two sessions in which they received pretreatment with either 0 or 15 mg oral d-amphetamine 2 h prior to completing the modified progressive-ratio procedure. d-Amphetamine produced prototypical stimulant-like effects (e.g., increased ratings of stimulated, elevated blood pressure) and maintained responding on the modified progressive-ratio schedule. Pretreatment with 15 mg oral d-amphetamine also produced prototypical stimulant-like effects, but failed to alter break points for d-amphetamine on the modified progressive-ratio procedure relative to placebo pretreatment. These results indicate that acute d-amphetamine pretreatment does not increase stimulant self-administration.

Tcheremissine OV. Is quetiapine a drug of abuse? Reexamining the issue of addiction. (review). Expert Opinion on Drug Safety 7(6): 739-748, 2008. (92 refs.)

Background: The abuse and diversion of pharmacological agents with CNS mechanisms of action is an important concern from governmental, regulatory, public health and safety perspectives. In recent years, there have been an increased number of reports concerning the abuse and diversion of quetiapine in forensic population and in individuals with histories of substance abuse. Objective: To better understand this surging pattern the available body of evidence was critically examined. Methods: A literature search from January 1991 to July 2008 restricting papers to English and using PUBMED and PsychInfo was performed. Results: Nine papers were identified. The content of these papers is discussed in light of recent research on drug abuse.

Uhlmann C; Froscher W. Low risk of development of substance dependence for barbiturates and clobazam prescribed as antiepileptic drugs: Results from a Questionnaire Study. CNS Neuroscience & Therapeutics 15(1): 24-31, 2009. (29 refs.)

There is no systematical research about the topic of dependence on antiepileptic drugs (AED) for patients with epilepsy, despite the fact that barbiturates and benzodiazepines comprise a potential risk of dependence. We hypothesize that there is no psychological substance dependence for patients with epilepsy, possibly because of their outcome expectations. The aim of the study was to examine these patients in terms of substance dependence. One hundred inpatients at the Lake Constance Epilepsy Center were asked about their experiences with AED in terms of dependence in a structured interview. We registered general statements about dependence of AED, markers for substance dependence, and outcome expectations. About 50% of the patients reported withdrawal symptoms and the development of tolerance, but less than 10% noticed loss of control and craving. Withdrawal symptoms and development of tolerance were significantly lower in a group of patients without barbiturates or clobazam versus patients with barbiturates or/and clobazam. There was no significant difference between these two groups in psychological criteria of dependence, that is, loss of control and craving. Outcome expectations of AED were clearly related to the efficacy against seizures, and only to a small amount to psychotropic effects. The study demonstrates that physiological variables of dependence are present more in patients with epilepsy with a permanent intake of barbiturates or clobazam, but psychological variables of dependence are rarely present in epileptic patients, with or without an intake of barbiturates and clobazam. These results confirm our hypothesis that substance dependence is not a major problem in benzodiazepines and barbiturates in patients with epilepsy. Outcome expectations seem to be related mainly to the anticonvulsant and not the psychotropic effect. This might be the reason for the absence of dependence.

Victorri-Vigneau C; Dailly E; Veyrac G; Jolliet P. Evidence of zolpidem abuse and dependence: results of the French Centre for Evaluation and Information on Pharmacodependence (CEIP) network survey. British Journal of Clinical Pharmacology 64(2): 198-209, 2007. (62 refs.)

To show that the nonbenzodiazepine hypnotic zolpidem has a higher abuse potential than previously documented. An official enquiry was carried out by the Nantes Centre for Evaluation and Information on Pharmacodependence (CEIP). The authors made a review of literature and analysed French data corresponding to the drug's postmarketing period collected by the CEIP network from 1993 to 2002. The literature review yielded mixed results concerning the behavioural effects of zolpidem. Data from the CEIP and the 53 literature case reports highlight significant dependence and abuse potential of zolpidem. This study adds to the growing evidence that zolpidem has the potential for abuse and dependence. As a consequence, the French drug monograph has been modified by the French Health Authorities.

Walsh SL; Nuzzo PA; Lofwall MR; Holtman JR. The relative abuse liability of oral oxycodone, hydrocodone and hydromorphone assessed in prescription opioid abusers. Drug and Alcohol Dependence 98(3): 191-202, 2008. (38 refs.)

Abuse of prescription opioids has risen precipitously in the United States. Few controlled comparisons of the abuse liability of the most commonly abused opioids have been conducted. This outpatient study employed a double-blind, randomized, within-subject, placebo-controlled design to examine the relative abuse potential and potency of oral oxycodone (10, 20 and 40mg), hydrocodone (15, 30 and 45 mg), hydromorphone (10, 17.5 and 25 mg) and placebo. Healthy adult volunteers (n = 9) with sporadic prescription opioid abuse participated in I I experimental sessions (6.5 h in duration) conducted in a hospital setting. All three opioids produced a typical mu opioid agonist profile of subjective (increased ratings of liking, good effects, high and opiate symptoms), observer-rated, and physiological effects (miosis, modest respiratory depression, exophoria and decrements in visual threshold discrimination) that were generally dose-related. Valid relative potency assays revealed that oxycodone was roughly equipotent to or slightly more potent than hydrocodone. Hydromorphone was only modestly more potent (less than two-fold) than either hydrocodone or oxycodone, which is inconsistent with prior estimates arising from analgesic studies. These data suggest that the abuse liability profile and relative potency of these three commonly used opioids do not differ substantially from one another and suggest that analgesic potencies may not accurately reflect relative differences in abuse liability of prescription opioids.

Wright C; Schnoll S; Bernstein D. Risk evaluation and mitigation strategies for drugs with abuse liability public interest, special interest, conflicts of interest, and the industry perspective. Annals of the New York Academy of Sciences 1141(Addiction Reviews 2008): 284-303, 2008. (48 refs.)

Risk evaluation and mitigation strategies (REMS) formerly known as Risk Minimization Action Plans (RiskMAPs) are a regulatory technique for dealing with anticipated risks of new medications and are especially important for new drugs with abuse potential. This paper describes the origin and history of risk-management plans for drugs that might be abused, the proper use of these plans in minimizing the risk to the public, and the special difficulties inherent in managing risks for drugs with abuse potential. Drugs with abuse liability are distinctive since the risks inherent in manufacture and distribution include not only risks to patients prescribed the medications, but also risks to the general public including subgroups in the population not intended to get the drug and who receive no medical benefit from the medication. The crafting of risk-management plans intended to protect nonpatient populations is unique for these products. The content, extent, and level of intensity of these plans affect areas of medical ethics, civil liability, and criminal prosecution. The need for risk-management plans for drugs with abuse liability can potentially act as a deterrent to investment and is a factor in decisions concerning the development of new medications for the treatments of pain, ADHD, anxiety disorders, and addictions. This paper provides a framework for moving the process of REMS development forward and criteria for evaluating the probity and adequacy of such programs.

Younis AA; Moselhy HF. Benzhexol-dependence resulting from self-medication for intermittent explosive disorder. International Journal of Psychiatry in Clinical Practice 13(1): 11-15, 2009. (29 refs.)

Objective. Recent observations in Iraq during the period of sanction suggest the existence of benzhexol prescribing linked to its calming effects on explosive behaviours. This inspired our group to research the existence of this practice and the characteristics of those involved in it. Method. All patients from the psychiatric service in Merjan Hospitalital, Al Hilla City, Babylon Governate, Iraq, who had a prescription for benzhexol between January 1991 and December 2000, were identified. All participants received their diagnosis based on the clinical criteria of the DSM-IV, after taking a comprehensive medical and psychiatric history, mental state examination and collateral information from family members. The patients were evaluated by the same qualified consultant psychiatrist at the initial assessment and all through the period of follow-up. Results. In the 10-year period under study, 354 patients were prescribed benzhexol. A total of 190 patients diagnosed as intermittent explosive disorder (IED) and 164 suffering from severe mental disorders or personality disorders were excluded from the study. The average age of the IED group was 29.5 years. On direct questioning, the main reason patients gave most frequently for using benzhexol was to control the aggressive outbursts (N=92, 48.4), to get high (N=49, 25.8), to relax (N=26, 13.7), to get rid of boredom (N=23, 12.1). In total, the whole group were prescribed benzhexol, at an average dose of 12.5 mg/day (range 2-20 mg/day). At the time of final assessment the mean dose of prescribed benzhexol had fallen slightly to 12 mg/day (2-20 mg/day), with 10 patients being benzhexol free. Of the 190, three patients had a diagnosis of obsessive compulsive disorders, 36 patients had a diagnosis of benzodiazepines dependence, and a further five had a diagnosis of alcohol dependency syndrome. Eighty percent felt satisfied with the effect of the drug and 95 were not motivated to stop it. Conclusions. There are a significant number of patients who are routinely prescribed benzhexol as a replacement therapy. The main original reason for starting it is to control outbursts and improves their reaction to stress situations. This growing issue raises the need for awareness, by both public and medical practitioners, of the potential adverse effects of benzhexol and its untoward consequences.

Zacny JP; Lichtor SA. Within-subject comparison of the psychopharmacological profiles of oral oxycodone and oral morphine in non-drug-abusing volunteers. Psychopharmacology 196(1): 105-116, 2008. (56 refs.)

Rationale: Nonmedical use and abuse of prescription opioids is a significant problem in the USA. Little attention has been paid to assessing the relative psychopharmacological profile (including abuse liability-related effects) of specific prescription opioids. Objectives The aim of this study is to directly compare the psychopharmacological profile of two oral opioids within the same subject. Methods A randomized, placebo-controlled, crossover study was done in which 20 non-drug-abusing volunteers ingested 10 and 20 mg of oxycodone, 30 and 60 mg of morphine, and placebo in separate sessions. Drug doses were equated on an objective measure of opiate effects: miosis. Subjective, psychomotor, reinforcing, and physiological effects of the opioids were assessed. Results In general, the two opioids at equimiotic doses produced similar prototypic opiate-like effects and psychomotor impairment of similar magnitude. However, several effects were found only with 20 mg oxycodone. Both drugs produced abuse liability-related subjective effects but also dysphoric effects, particularly with 60 mg morphine. Neither drug at either dose functioned as a reinforcer, as measured by the Multiple Choice Procedure. Relative potency ratios indicated an average oxycodone:morphine ratio of 3:1. Conclusions: The psychopharmacological profile of oxycodone and morphine at equimiotic doses had many similarities; however, differences were found in producing abuse liability-related and dysphoric effects. In the medical community, it is commonly accepted that oral oxycodone is 1.5 to 2 times as potent as oral morphine in producing analgesia; using this ratio, although patients may experience similar degrees of pain relief, those receiving oxycodone may be experiencing stronger and potentially different psychopharmacological effects.

Zacny JP; Walker DJ; Derus LM. Choice of nitrous oxide and its subjective effects in light and moderate drinkers. Drug and Alcohol Dependence 98(1/2): 163-168, 2008. (23 refs.)

Background: Alcohol-drinking status has been shown to modulate the reinforcing and subjective effects of a number of drugs. We have previously published two studies on the modulating effects of alcohol-drinking status on choice for, and subjective effects of, nitrous oxide, but the results were equivocal. Using a methodology different from our previous studies, we sought to determine in a more definitive fashion the degree to which the choice of nitrous oxide and its subjective effects were modulated by drinking status. Methods: Four concentrations of nitrous oxide (0, 20, 30, and 40%) were administered to 16 moderate drinkers (MDs) and 16 light drinkers (LDs) across four 3.5-h sessions. During experimental sessions, subjects first completed two 10-min sampling trials in which one of the nitrous oxide concentrations and placebo (100% oxygen) were inhaled. Subjective and psychomotor tests were given 5�min into each sampling trial. During the subsequent choice period, subjects were allowed to choose what they wanted to inhale (drug, placebo, or "drug-free air") on nine contiguous 5-min choice trials. Results: Choice of nitrous oxide was modulated by drinking status: MDs but not LDs chose nitrous oxide significantly more times than placebo, and MDs also chose nitrous oxide significantly more times than did LDs. At each active nitrous oxide concentration, MDs reported more abuse liability-related subjective effects, especially at the 20% and 30% concentrations. Conclusions: The results of the present study provide more conclusive evidence that choice as well as subjective effects of nitrous oxide is modulated by alcohol-drinking status.