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Nalfurafine (nalfurafine hydrochloride, TRK-820, Remitch®) was launched as an anti-pruritic for uremic pruritus in hemodialysis patients in Japan in 2009. Since the drug is an opioid that mainly binds to κ-receptors and possesses κ-agonistic pharmacological properties and also binds partially, but very weakly, to μ-receptors, the abuse liability of the drug was assessed by using questionnaires in patients enrolled in a clinical trial evaluating the efficacy and safety of the drug. The clinical trial was conducted for up to 52 weeks in patients subjected to regular hemodialysis. End-stage renal disease (ESRD) patients with uremic pruritus (n = 146) were administered nalfurafine 5 μg intravenously after each hemodialysis session. 81 ESRD patients without uremic pruritus served as non-treatment controls. All pruritus patients answered the 3 questionnaires of "the Addiction Research Centre Inventory (ARCI)", "modified Short Opiate Withdrawal Scale (SOWS)", which provides a range of signs and symptoms of opiate withdrawal, and Severity of Dependence Scale (SDS), which measures the dependence potential of the drug. The control patients were tested with the ARCI and modified SOWS questionnaires. There were no significant differences between the nalfurafine group and control group in the ARCI and modified SOWS scales. Thus, no evidence of abuse liability was indicated in the results. Also, no significant differences in the blood pressure, respiratory rate, body temperature and pupil diameter were shown between the two groups.

The purpose of the present study was to observe the psychosocial characteristics of withdrawal from cigarette smoking in comparison with those from caffeine (CAF) and alcoholic (ALC) beverage withdrawal. Twenty-seven healthy volunteers at a medial level of dependence on both cigarettes (nicotine, NCT) and either CAF or ALC, as judged by the DSM-IV-TR criteria for substance dependence, participated in this study. The participants were required to abstain from smoking and either CAF or ALC for 7 days, each one after another, with a 7-day interval. The order of abstinence was counterbalanced among the participants. Psychosocial parameters, including a desire for substances, social activity function, well-being, withdrawal symptoms, and vital signs, were assessed during the withdrawal periods. The study protocol was approved by the Jikei University Review Board. The results indicated that there were no differences in the maximum level of desire for a substance and the influence on social activity function between NCT and other substances during the withdrawal periods. As for withdrawal symptoms, NCT caused a more intensive degree of irritability than CAF or ALC, and a more intensive degree of difficulty concentrating and restlessness than did withdrawal from ALC. However, the subjective well-being questionnaire indicated no differences in these symptoms between NCT and other substances. The present results suggest that there are no significant differences in psychosocial manifestations regarding the difficulty in abstaining from NCT, CAF, and ALC.

A new clinical evaluation form was developed to compare the clinical features of nicotine dependence with those associated with other abused drugs. A new scoring system for clinical evaluation was developed. The form consisted of five scoring items: subjective effects, liking (of drug), withdrawal syndrome, acute psychic and physical disorders, and social disturbance. A preliminary clinical investigation was performed to test the validity of the evaluation form. Study subjects were those showing dependence on nicotine (cigarette smoking, n = 40), alcohol (n = 39), methamphetamine (n = 31), and inhalants (n = 30), who fulfilled the DSM-IV-TR criteria for drug dependence disregarding the state of "a maladaptive pattern of substance use, leading to clinically significant impairment or distress," and gave written informed consent for participation in the study. Nicotine caused a mild or the least degree of subjective effects, liking, and psychic and physical withdrawal symptoms, without any significant social disturbance or acute disorders. With alcohol, liking, withdrawal syndrome, and acute physical disorders were prominent. Methamphetamine produced the most serious acute psychic disorders, with intensive acute physical disorders and psychic withdrawal symptoms. Inhalants were characterized by an intensive degree of acute psychic disorders. As for social disturbance, alcohol, methamphetamine, and inhalants showed more significant influence than nicotine. Our study findings revealed that the clinical features of drug dependence could be evaluated by using the new clinical evaluation form. Further study is required to clarify the clinical features of nicotine dependence compared with those of other drugs of dependence.

The purpose of the present study was to develop a new clinical evaluation form to compare the clinical features of nicotine dependence with those associated with alcohol, methamphetamine, and inhalant dependence. The clinical evaluation form consisted of six scoring items: subjective effects, tolerance, liking (of drug), social disturbance, withdrawal syndrome, and acute psychic and acute physical disorders. A preliminary clinical investigation was performed to test the validity of the evaluation form. Study subjects were those showing dependence on nicotine ( n = 25), alcohol ( n = 36), methamphetamine ( n = 11), and inhalants ( n = 6). All subjects met the Diagnostic and Statistical Manual of Mental Disorders (4th ed.) diagnostic criteria for drug dependence, as defined by the Work Group for the chapter "Substance-Related Disorders": M. A. Schuckit, J. E. Helzer, L. B. Cottler, T. Crowley, P. E. Nathan, & G. E. Woody. Nicotine produced subjective effects, tolerance, liking, and psychic withdrawal symptoms, all of which were mild in degree. However, nicotine did not produce social disturbance, physical withdrawal symptoms, or acute psychic or acute physical disorders. With alcohol, acute psychic and acute physical disorders were prominent, and alcohol also produced a moderate degree of influence on various other items that were evaluated. Methamphetamine produced the most serious acute psychic and acute physical disorders with intensive subjective effects. Inhalants were characterized by an intensive degree of acute psychic disorders and subjective effects with mild withdrawal syndrome. Our study findings revealed that the clinical features of drug dependence could be evaluated by using the new clinical evaluation form. Further study is required to clarify the clinical features of nicotine dependence compared with those of other drugs of dependence.

The technical term 'drug dependence' was officially adopted by WHO's Expert Committee on Addiction in 1964. Until this, to describe a state of dependence, terms such as 'poisoning', 'habit', 'ism', and 'addiction' had been used from time to time. Until the 1950's, investigators were mainly focussed on the phenomena of physical dependence. However, once the concept of psychic dependence had been introduced, behavioral and neuropharmacological studies on the modes of drug action that produce psychic dependence were activated and have progressed in the last two decades, and among the points clarified by these studies are the following: 1. The critical drug properties that produce psychic dependence are those of rewarding subjective and reinforcing effects of drugs but these effects are not the properties that produce physical dependence, although the development of physical dependence on particular drugs such as opiates may substantially enhance craving for the drugs. 2. The mesolimbic and mesocortical dopamine systems in the brain and also the N. Accumbens play a primary or at least a partial role in producing the subjective and reinforcing effects of major dependence-producing drugs such as cocaine, opiates, barbiturates, benzodiazepines, and ethanol. 3. Many drugs such as naltrexone, methadone, and some dopamine antagonists and serotonin reuptake inhibitors or antagonists were found to be effective in the pharmacotherapy of the dependence on opiates, cocaine, or ethanol.

It is a pleasure for us to introduce the Proceedings of the Satellite Symposium on Nicotine and Alcohol of The 10th Congress of the International Society for Biomedical Research on Alcoholism (ISBRA). The Satellite Symposium was held in Yokohama, Japan, on July 8, 2000. Leading scientists from around the world whose research efforts have focused on nicotine in the tobacco habit and drug dependence participated in the Satellite Symposium. There were 13 papers presented at the meeting, and 12 of those 13 papers are included in this Special Issue. These papers covered most of the major areas of biomedical research on nicotine effect and dependence. The Symposium was structured around three themes: nicotine and brain function, clinical studies on smoking, and biological mechanisms of drug dependence. Both the molecular and genetic mechanisms of, and the differences in clinical features associated with, nicotine dependence, as well as those of other drugs of dependence, were presented and discussed. Both lectures and question-and-answer sessions were stimulating and enlightening. We are grateful to all participants for the excellence of their contributions to the Symposium. I would like to extend our sincere thanks to all the sponsors who generously supported this Satellite Symposium, as well as to Thomas R. Jerrells, Editor-in-Chief of Alcohol, for his valuable advice and cooperation during the publication process of this Special Issue of Alcohol. Because it is the editorial policy of Alcohol that all manuscripts submitted for publication be peer-reviewed before acceptance for publication, we would especially like to extend our thanks to Dr. Jerrells and Janice Jerrells, Managing Editor for Alcohol, for arranging for peer-review of all the manuscripts, as well as to the reviewers who provided their time and expertise to review these manuscripts.

The drug dependence potential of viloxazine was tested in 5 experiments on rhesus monkeys. In gross behavioral observation of normal monkeys the acute CNS effects of the drug were found to be very weak. Decrement of spontaneous motor activity and occasional eye-closing were observed with single doses higher than 16 mg/kg IV, IM and 128 mg/kg PO, while convulsions and death occured at 64 mg/kg IV and IM. Viloxazine did not suppress the morphine and barbital withdrawal signs in monkeys that had been made physically dependent on these drugs and withdrawal. In the test for physical dependence by repeated administration of the drug at 16 mg/kg IM twice daily for 31 days in normal monkeys, no observable withdrawal sign was developed in the naloxone precipitation and natural withdrawal tests. In intravenous self-administration experiments, a weak reinforcing effect was demonstrated in some monkeys, but the effect was extremely weak. Thus, viloxazine was found to be physical dependence-free and its overall dependence potential was regarded as very low.

Risk assessment of dependence-producing drugs comprises assessment of two major risks: the risk that a drug is likely to be abused (abuse liability) and the harm that is likely to occur as a consequence of abuse (termed here as harm liability). Important determinants of these risks are the dependence-related pharmacological and toxicological properties of a drug. In this paper, the relationships of the drug properties to the abuse and harm liabilities are described. Next, a scoring system to assess the abuse and harm liabilities is introduced. Finally, an attempt to actually apply this system to several prototypic drugs of abuse and some agonist-antagonist analgesics is explained.

Drug depenence liabilty of 5 tricyclic antidepressants, imipramine, imipramine-N-oxide, protriptyline, maprotiline and iprindole, were examined using rhesus monkeys. In gross behavioral observations of acute central nervous system effects in normal monkeys, imipramine, protriptyline, maprotiline and iprindole produced a decrease of awareness, mydriasis, ataxia, tremor and convulsions, but imipramine-N-oxide did not. In cross intravenous self-administration of the drugs with a standard stimulant and saline, no meaningful reinforcing effect on monkeys' drug-seeking behavior was observed with any drug, with the exception of one of the 4 monkeys with iprindole. In the continuous self-administration test, positive self-administration was observed in 2 out of 4 monkeys with imipramine and in one monkey each with imipramine-N-oxide, protriptylin and iprindole. But the self-administration rates were considerably low in comparison with that of principle drugs of abuse and none of these monkeys manifested observable drug effects. No monkey showed positive self-administration of maprotiline. Thus, the amphetamine-like dependence liability was not found in these drugs.

In the drug dependence liability studies, 4 tests were conducted. In the test on acute CNS effects of the drug, normal monkeys did not show any meaningful or physical changes with single oral doses of the drug at 50, 100, 200, 400, and 500 mg/kg.In the test of substitution of Clonixin for morphine in morphine dependent and withdrawn monkeys, single oral doses of the drug at 20, 50, 100, and 200 mg/kg did not suppress morphine withdrawal signs, and thus did not support physical dependence on morphine.In the physical dependence producing test on Clonixin, repeated oral administration of the drug to naive monkeys at daily doses of 100, 200, and 400 mg/kg for 4 weeks did not produce any physical dependence as observed by naloxone tests.In the intragastric self-administration test in drug seeking behavior conditioned monkeys, Clonixin did not positively reinforce the drug seeking behavior. Thus, Clonixin was found to be dependence free.In the teratogenicity test, 2 pregnant monkeys received 30 mg/kg, 2 other pregnant monkeys received 200 mg/kg, and one pregnant monkey received the vehicle alone, daily by gavage for 7 days, from the 23rd to 29th day of pregancy. All fetuses were removed from the uteruses by cesarean section on 59th, 60th or 61 st day of gestation. Detailed examinations of the fetuses revealed no abnormalities at all in external morphological appearance, visceral organs, or skeletal structures.

Sedative-hypnotic type drug dependence liability of B 169, a new anticonvulsant, was studied in rhesus monkeys.In gross behavior observation of acute CNS effects by single oral doses of 500 and 1000 mg/kg, no meaningful effect was observed. At 2000 mg/kg, a slight decrease of spontaneous motor activity and of awareness to outer stimuli was observed one hour after administration. The monkeys, however, reacted normally to man without any impairment of motor function.In the cross physical dependence test in monkeys made, physically dependent on barbital and then withdrawn, the drug did not support the dependence when it was substituted for barbital at single oral doses of 1000 or 2000 mg/kg.When drug seeking behavior conditioned monkeys were allowed to self-administer the drug intragastrically by pressing a lever switch in the cage without time or dose limitation, none of the animals voluntarily ingested the drug. Since they did not initiate self-administration, timer-programmed forced infusion of the drug into the stomach was conducted at a dose regimen of 20 mg/kg/infusion every 6 hours for 2 weeks. Initiation of self-administration was still not observed during or after the programmed administration period. No withdrawal signs were observed at the termination of programmed administration.Thus, B169 was found to be dependence free.

Barbiturate-like drug dependence liability of Calcium N-2-ethylhexyl-β-oxybutyramide semisuccinate (M-2), a new synthetic sedative-hypnotic agent, was studied in rhesus monkeys.In gross behavior observation of acute CNS effects, the compound did not show as strong CNS depressant effects in monkeys as it had in small animals.A physical dependence producing test was conducted by oral administration of the compound 4 times a day, for 4 weeks at dose levels of 100, 200, or 400 mg/kg/day, with 2 naive monkeys for each dose level. At the end of 4 weeks, administration was terminated and a withdrawal test was conducted for 5 days. No meaningful withdrawal signs were observed. On the other hand, oral administration of barbital for 4 weeks produced intermediate to severe grade withdrawal signs in other monkeys.In cross intravenous self-administration of M-2, a CNS stimulant and saline in self-administration conditioned monkeys, the compound did not show drug seeking behavior reinforcing effects at unit doses of 0.25, 1.0, and 4.0 mg/kg/inj..Because of the lack of CNS depressant effects, ability of producing physical dependence and drug seeking behavior reinforcing effects, the potency of dependence liability of M-2 was concluded as practically none.

In this chapter, the pharmacological factors involved in predicting the abuse liability of drugs are discussed with major emphasis on their psychological dependence potential. For prediction of drug abuse liability, it is important to find and compare the drug’s effects against those of prototypic drugs. The important pharmacological properties include the following: central nervous system (CNS) effects, including operant behavioral effects; tolerance; physical dependence potential; and psychological dependence potential. It is also important to consider such chemical and pharmacokinetic properties as water solubility and speeds of absorption and elimination. In particular, psychological dependence potential is most relevant to abuse liability. To evaluate psychological dependence potential from animal studies, the reinforcing and discriminative stimulus properties of drugs must be assessed in comparison with those of prototypic drugs. When human data are available, it is important to verify the animal results on such points as pharmacokinetics and CNS drug susceptibility which may differ across species.