[Helping the "hard-core" smokers]. / Le sevrage tabagique des "fumeurs difficiles".

Smoking cessation specialists are frequently confronted with smokers who have great difficulty in stopping smoking, and who are either motivated to stop or are forced to stop for health, economic or statutory reasons. These smokers are composed of a mixed population but they have in common a heavy dependence on tobacco and a significant level of cigarette consumption. They are exposed to serious morbidity induced by their uncontrollable smoking. Other factors unfavourable to the attempt to stop smoking are often present: anxiety-depressive disorders, socioeconomic difficulties or the use of psychoactive substances. They constitute a priority target for smoking cessation clinics, which must optimise and diversify proposals to improve their interventions. This review describes these highly dependent smokers unable to stop, and suggests medical treatments and therapeutic combinations to assist the practitioners trying to help the "hard-core" smokers.

[Tests for evaluating tobacco dependence]. / Les tests d'évaluation de la dépendance tabagique.

The primary reason why there is such a heavy burden of tobacco smoking induced illness and death is dependence on nicotine which makes it difficult for smokers to quit. For clinical or research purposes, the degree of dependence, the intensity of the withdrawal syndrome and/or craving have been evaluated by different scales. This review provides a list of questionnaires that are used in smoking cessation. It pays particular attention to the validated and translated resources that are available in French. Research should be conducted in order to provide French speaking smoking cessation specialists with all the relevant scales allowing better evaluation of tobacco dependence.

Chronic high dose transdermal nicotine in Parkinson's disease: an open trial.

Whether nicotine has therapeutic effects on Parkinson's disease (PD) symptoms is controversial, but high doses and chronic treatment have never been tested. We report the results of a pilot, open-label trial to assess the safety and possible efficacy of chronic high doses of nicotine. Six patients with advanced idiopathic PD received increasing daily doses of transdermal nicotine up to 105 mg/day over 17 weeks. All patients but one accepted the target dose. Nausea and vomiting were frequent but moderate, and occurred in most of the patients (four of six) who received over 90 mg/day and 14 weeks of nicotine treatment. During the plateau phase, patients improved their motor scores and dopaminergic treatment was reduced. These results confirm the feasibility of chronic high dose nicotinic treatment in PD but warrant validation of the beneficial effects by a randomized controlled trial.

[What smoking cessation interventions are effective in pregnant women?]. / Quelles sont les interventions efficaces d'aide à l'arrêt du tabac chez la femme enceinte?

Tobacco smoking during pregnancy is the single largest modifiable risk for pregnancy-related morbidity and mortality. Tobacco smoke contains thousands of chemicals, many of which may contribute to reproductive toxicity. Carbon monoxide is the most biologically significant toxin for the fetus. The use of nicotine replacement therapy is probably not without risk, although the magnitude of risk to the mother and fetus is much lower than continuing smoking. Most pregnant women are motivated to stop. It is, therefore, a good time to initiate smoking cessation as early as possible during pregnancy, and to maintain abstinence during post-partum to protect the infant from passive smoking. If behavioral intervention fail to produce abstinence, a sign of high dependence, nicotine replacement therapy should be initiated promptly. Although bupropion is not recommended during pregnancy, this therapy should be considered when contraindications are carefully observed. It is recommended that all patients treated with nicotine or bupropion be reported to a pregnancy registry that collects pregnancy and obstetrical outcome data. This registry would allow health professionals to share their experience and should encourage them to use pharmacotherapy more frequently and lift psychological barriers concerning its use in pregnant women.

Role of nicotine pharmacokinetics in nicotine addiction and nicotine replacement therapy: a review.

Smoking is a complex behaviour involving both pharmacological and psychological components. Nicotine is the main alkaloid found in tobacco, and is responsible for its addictive potential. Nicotine-positive effects on mood and cognition are strong reinforcements for smokers that contribute to their addiction, and cigarette smoking is particularly addictive because inhaled nicotine is absorbed through the pulmonary venous rather than the systemic venous system, and thus reaches the brain in 10-20 seconds. As the likelihood that a substance will be abused depends on the time between administration and central reinforcement, tobacco smoking can easily become addictive. Nicotine replacement therapy (NRT) is available in different forms (gum, transdermal patch, nasal spray, inhaler, sublingual tablet and lozenge), and has been shown to relieve withdrawal symptoms and to double abstinence rates compared to placebo. Most NRT forms deliver nicotine more slowly than smoking, and the increase in nicotine blood levels is more gradual. Compared to tobacco smoking or even tobacco chewing, few positive (reinforcing) effects are obtained from NRT use. Nasal spray provides faster withdrawal relief than other NRT, but compared to smoking absorption is slower and nicotine blood levels obtained are lower than with smoking. These differences in pharmacokinetic profiles compared with smoking may explain that some smokers still have difficulties quitting smoking even when using NRT (apart from psychological and/or social factors). Combination therapy (e.g., patch+gum, patch+inhaler), higher dosage, temporary abstinence or smoking reduction (using NRT to reduce smoke intake) may be needed to help more smokers to quit.

[Smoking reduction and temporary abstinence: new approaches for smoking cessation]. / Réduction de consommation tabagique et abstinence temporaire: de nouvelles approches pour l'arrêt du tabac.

Tobacco use causes enormous morbidity and mortality because of the high risk of smoking-related diseases and the high prevalence of cigarette smoking. Existing smoking cessation methods only help motivated smokers who are ready to quit, but the vast majority of smokers are pre-contemplators who are neither ready nor willing to attempt to quit. This means that a high proportion of smokers are not adequately served by current strategies for treating tobacco dependence. As cigarettes prematurely kill 50% of long-term users, any additional measure that may reduce death or illness should be given serious consideration. Many addicted smokers are now forced to live and work much of their life in environments in which smoking is prohibited. Most smokers are dependent on nicotine and abstinence from smoking results in tobacco withdrawal and craving, which manifest as clinical symptoms within a few hours of smoking the last cigarette. Craving and withdrawal symptoms can be controlled by supplying nicotine from sources other than cigarettes, such as Nicotine Replacement Therapy (NRT). Clinical studies of short-term abstinence show that all NRT formulations relieve tobacco withdrawal symptoms and craving. Most unaided attempts to decrease health risks by reducing smoking fail because smokers revert to their 'usual' nicotine intake. However, using NRT to reduce smoking allows smokers to reduce their cigarette consumption (and intake of toxic substances in smoke) while maintaining their nicotine dose. Data suggest that smokers who use NRT can significantly reduce the withdrawal symptoms and craving caused by abstaining from cigarettes, and thereby reduce the number of cigarettes/day and maintain these reductions for up to 2 years. The data also indicate that, despite some compensatory smoking behaviour, reduced smoking with NRT results in decreased toxin exposure. In smoking reduction studies, this translated into an improvement in variables that impact on health: cardiovascular risk factors and haemorheology parameters moved towards more healthy (i.e. non-smoker) levels, and pulmonary function improved. The improvements in established cardiovascular risk factors provide objective proof that exposure reduction translates into clinically meaningful health benefits. Furthermore, the known reversibility of many smoking-induced diseases, the mainly linear dose-effect curve and the absence of any indication of threshold effects suggest that additional health benefits may result from smoking reduction. Even more importantly, smoking reduction may move smokers along the behavioural model towards the ultimate goal--stopping smoking. In all three large smoking reduction studies, a number of subjects who were unwilling or unable to stop smoking at baseline were abstinent at 4 months and 1 and 2 years, which clearly supports the concept of smoking reduction as a step towards abstinence. Rather than undermining cessation, smoking reduction appears to increase motivation to quit. The importance of allowing smokers to gradually take control of their smoking was reflected by the increasing point prevalence abstinence rates seen in the long-term studies. When encouraging smoking reduction, it should clearly be emphasised that complete cessation remains the ultimate goal, but smokers in the precontemplation stage need to progress along the behavioural model before becoming receptive to messages about quitting. In conclusion, the evidence presented in this review supports reduced smoking as a legitimate treatment approach that could be pursued by those smokers who are currently unable or unwilling to quit. Sustained smoking reduction can be achieved and maintained with NRT. The corresponding reduction in exposure is associated with tangible health benefits, measured using surrogate markers. Smoking reduction also promotes abstinence in smokers who are unable or unwilling to quit smoking abruptly. NRT is well tolerated for smoking reduction, and nicotine intake does not increase during concomitant use of NRT and smoking.

Early emotional disturbances during nicotine patch therapy in subjects with and without a history of depression.

BACKGROUND: The goal of this study was to compare development of emotional symptomatology during smoking cessation with transdermal nicotine patches in subjects with and without a history of depression. METHODS: Twenty-five subjects, 14 with a history of depression and 11 without such a history, were evaluated before beginning of cessation, on day 8, day 30, day 90 and day 120. RESULTS AND DISCUSSION: On day 120, ten subjects have maintained abstinence: 71.4% of subjects with and 45.5% of subjects without a history of depression relapsed. Both groups presented variable emotional symptomatology and there was no significant differences between subjects with and without a past depression. On the other hand, none of the symptoms which emerged during cessation predicted the issue of cessation. However, some symptoms appearing before beginning of cessation were related to subsequent relapse: lack of pleasure seeking and tiredness. Subsequent relapsers also tended to be more tense on baseline. These early symptoms can not be considered as withdrawal symptoms, they may reflect less confidence in success. It is also suggested that development of anhedonia represents an adaptative strategy to prepare for the withdrawal suffering.

Relationships between sensation seeking and emotional symptomatology during smoking cessation with nicotine patch therapy.

This study explored relationships between the sensation-seeking trait and the development of emotional symptomatology during smoking cessation with nicotine transdermal patches. Twenty-five subjects were evaluated before they stopped smoking, on Day 8, Day 30, Day 90, and Day 120. Initial motives for smoking and the sensation-seeking personality trait were tested as possible predictors for the development of specific mood disturbances. Our subjects scored very high on sensation seeking, consistent with previous results on smokers. This may also be due to the well-known tendency of high sensation-seekers to be willing to try new experiences. The sensation-seeking trait did not predict the issue of cessation. However, it was related to emotional deficit (anhedonia, affective blunting), tiredness, and a lack of energy, before and during smoking cessation. Two different interpretations of emotional deficit are proposed.

Frontal reactivity and sensation seeking an ERP study in skydivers.

1. In the line of Zuckerman's studies on sensation seeking and optimal level of arousal, the authors hypothesized that high sensation seeking might be used to compensate for anhedonia due to basal arousal deficit. A population of interest was found with parachutists practicing skydiving, generally described as very high sensation seekers. 2. After clinical assessment of emotional and affective components, amplitudes of the frontal P3 of the ERP were used as indices of arousal. 3. Skydivers presented more negative symptoms (anhedonia and blunted-affect) than controls. This was observed in isolation from any depressive episode, which would suggest the presence of emotional deficit as a trait. As expected, skydivers presented more sensation seeking than controls. These two results taken together could indicate that sensation seeking is an adaptive reaction to anhedonia. 4. ERP results showed that frontal P3 amplitudes were larger in skydivers than in controls, whereas in a previous study we showed the opposite in depressed patients with a similar emotional deficit. This could indicate that the frontal P3 amplitude does not reflect the emotional deficit per se. We suggest that it rather reflects the capacity to use some behaviors which improve automatic attentional processes in order to obtain arousing stimulation that could counterbalance the emotional deficit. Depressions with emotional deficit might be due to the lack of such a capacity.

Dimensional assessment of onset of action of antidepressants: a comparative study of moclobemide vs. clomipramine in depressed patients with blunted affect and psychomotor retardation.

The onset of action (during the first 2 weeks of treatment) of moclobemide (450 mg/day), a reversible MAO-A inhibitor, was compared in a double-blind, multi-center trial with clomipramine (150 mg/day) on dimensional and global depressive symptoms in 124 hospitalized patients suffering from a major depressive episode according to DSM-III-R criteria and with blunted affect and retardation. An earlier efficacy was found for moclobemide with significant treatment differences in favor of moclobemide, which were detected on negative symptoms (anhedonia, blunted affect and retardation) on days 7 and 10. The overall effect on depression at the end of the 4-week trial period was similar in both groups. However, a higher termination rate due to lack of efficacy was found with moclobemide (10 vs. 3). The tolerability was significantly better for moclobemide, as shown by the lower frequency of adverse events.

Nicotine: abused substance and therapeutic agent.

Tobacco dependence is a complex phenomenon that is not fully understood. Nicotine is the main alkaloid in tobacco and the addictive compound of tobacco. It can improve both mood and cognitive functioning; these positive effects are strong reinforcements for smokers and contribute to their addiction. Opposite results also have been reported, however, and the effects of nicotine remain controversial. Recent epidemiological and empirical studies have indicated that smoking or nicotine or both may have protective effects against certain diseases. These findings have suggested that nicotine may be used as a therapeutic agent. However, because a variety of nicotinic cholinergic receptors are present in the brain, new agonist compounds may prove to be more effective than nicotine for therapeutic purposes. Studies are reviewed and the suggestion made that nicotine may prove useful as a tool to help us understand normal and pathological brain functioning.

Cognitive and emotional deficits in early stages of HIV infection: an event-related potentials study.

1. In order to inventory different Event-Related Potentials (ERP) modifications in HIV-infection the authors have evaluated 23 HIV-positive subjects and 12 HIV-negative subjects. ERP were recorded during an auditory oddball task. 2. Electrophysiological results showed that the latency of the N100 component of the ERP was significantly increased in HIV-positive subjects compared to the HIV-negative subjects. The latency of the N200 component of the ERP showed a similar tendency which just failed to reach significance when considering HIV-positive subjects vs HIV negative subjects. This result was in agreement with the literature which reported increased latencies in HIV infection. 3. Considering all subjects the authors have observed a correlation between the amplitude of the P300 and the emotional deficit. This correlation was stronger in subjects who presented an emotional deficit and was independent of any other psychopathological symptom. 4. The use of ERP appeared to be a sensitive technique to detect subclinical manifestations in HIV asymptomatic subjects and therefore would help to identify subjects at higher risk for developing cognitive impairments.

A low dose of subcutaneous nicotine improves information processing in non-smokers.

Many studies have found that cigarette smoking or nicotine improves mental functioning in abstinent smokers. An unresolved issue is whether this improvement is due primarily to a direct facilitation of performance or to relief of the impairment caused by nicotine withdrawal. We evaluated the performance of 12 non-smokers before and twice (15 and 45 min) after a subcutaneous injection of 0.8 mg nicotine, 0.8 ml saline, and a control no treatment, on a choice reaction time (RT) task. Each treatment was given on a separate day; the control day was given on the first session. The order of nicotine and saline was balanced between subjects, and injections were given double-blind. The RT task manipulated stimulus and response processing. These manipulations consisted of two levels of stimulus complexity and two levels of response complexity, resulting in four task conditions. These manipulations along with latency measures of the event-related potential were used to identify the components of processing that mediated nicotine's effects on performance. During each active drug session blood nicotine levels, cardiovascular, and subjective responses were measured before and after each of the three tests (pre-drug, 15 min and 45 min post-drug). For the information processing measures only the comparisons of the pre- and 15-min post-test showed significant drug effects. Nicotine compared to saline significantly increased the number of responses at the fast end of the RT distribution. However, there were no changes in accuracy. Nicotine also speeded mean RT compared with saline or the control day, but the effects were only significant for the control-nicotine comparison.(ABSTRACT TRUNCATED AT 250 WORDS)

A clinical pharmacological study of subcutaneous nicotine.

The stable isotope-labeled compound 3',-3'-dideuteronicotine (nicotine-d2) was used to investigate the disposition kinetics and effects of nicotine administered subcutaneously to 6 smokers. Plasma nicotine-d2 concentrations were measured for 8 h after subcutaneous injection of 4 doses (0.4, 0.8, 1.2, and 2.4 mg). Peak plasma nicotine concentration correlated well with the dose, averaging 2.8 to 14.8 ng/ml, 19 to 25 min after injection of the 0.4 mg and 2.4 mg doses, respectively. The plasma clearance over bioavailability ratio (CL/f) averaged 12 to 13 ml.min-1.kg-1, similar to the clearance reported previously for intravenously administered nicotine. Thus, bioavailability appears to be approximately 100%. The heart rate response was more sensitive to the nicotine dose than the blood pressure response. Subjective effects showed large interindividual variability. The results reported herein may be useful in planning future studies. Administration of nicotine by the subcutaneous route appears to be a practical and safe method for studying the human pharmacology of nicotine.

Basic and clinical psychopharmacology of nicotine.

Nicotine acts on nearly every physiological system of the human body. While the actions of nicotine on the autonomic nervous system may be of interest in understanding possible deleterious long-term effects of smoking on the cardiovascular system, the actions of nicotine on the central nervous system are of the most interest in understanding why people smoke. Many studies of the effects of nicotine on human cognitive function have been performed. Improvement in attention, learning, reaction time, and problem solving have been reported. However, most of the results are inconclusive owing to methodologic problems. Whether the enhanced performance observed after smoking is attributable to relief of symptoms of abstinence or to a primary effect of nicotine on the brain is not clear. The pharmacodynamic effects of nicotine must be considered in the design of studies of the effects of nicotine on human performance. It is not known if the effects of nicotine on performance are subject to tolerance. The facilitation of performance, perceived as a reinforcement, may tend to lessen throughout the day, as do other effects of nicotine. Studies of chronic tolerance to the behavioral effects of nicotine are needed; comparisons between regular smokers and occasional smokers may be helpful. At present, the facilitatory actions of nicotine on human performance have been explained in terms of arousal. However, nicotine actions cannot be explained in terms of this single concept. Different processes, including attention, stimulus evaluation, and response selection, appear to be involved in the effect of nicotine on human information processing. Finally, one must consider that the predominant effects of nicotine may differ among individuals, as different people smoke for different reasons, and the motives for (rewards of) smoking may vary in different situations.

Failure of behavioral dependence induction and oral nicotine bioavailability in rats.

As failure to induce behavioral dependence to oral nicotine (0.31 mM) might be caused by taste aversion. Sixteen rats were presented nicotine around the taste aversion threshold (0.025 mM then 0.05 mM) as only source of fluid for 10 weeks. Eight of them had undergone portacaval anastomosis (PCA) to increase bioavailability of nicotine by preventing liver first-pass. Weekly choice sessions between nicotine and water demonstrated neither aversion nor preference for nicotine. In 10 control and 11 PCA rats accustomed to drink 0.31 mM nicotine, plasma nicotine was determined after 3 ml/kg intragastric nicotine-solution. In both groups, 0.05 mM nicotine did not lead to detectable levels but 0.31 mM nicotine led to peak levels higher than seen in man after smoking. Similar levels were recorded after spontaneous nicotine drinking in 8 isolated and 18 grouped normal rats accustomed to 0.31 mM nicotine. Drinking nicotine for at least 10 weeks did not induce behavioral dependence in these rats. This cannot be explained by poor nicotine bioavailability by oral route.