Temporal effects of nicotine nasal spray and gum on nicotine withdrawal symptoms

Nicotine nasal spray and nicotine gum have been found to be effective in relieving nicotine withdrawal symptoms. In this randomized single-blind study, 91 cigarette smokers were randomly assigned to a single 1 mg dose of active nicotine nasal spray (n = 29), active 4 mg nicotine gum (n = 31), saline placebo nasal spray (n = 16) or placebo gum (n = 15). Following overnight abstinence, subjects repeatedly completed visual analog scales for assessing nicotine withdrawal symptoms over 30 min preceding (time -30 min to time 0) and 120 min following a single dose of study medication. This sequence was performed 3 times during the day. Nicotine withdrawal symptoms were assessed on a 41-point visual analog scale (1 = no withdrawal, 41 = extreme withdrawal). At the initial session only, blood samples for serum nicotine levels were taken at baseline, then at 5, 10, 30 and 120 min following study drug administration. The mean (± SD) age of the subjects was 38.6 (±10.1) years, 48% were females, smoking rate was 24.5 (±7.8) cigarettes per day, and years of smoking was 19.9 (±10.0). A single 1 mg dose of nicotine nasal spray provided more immediate relief for craving for a cigarette compared to a single 4 mg dose of nicotine gum. Serum venous nicotine levels for the active nicotine nasal spray and nicotine gum were comparable at 5 and 10 min while the levels were higher for nicotine gum at 30 and 120 min. Changes in withdrawal symptoms were not found to be related to serum venous nicotine levels. Our findings provide a rationale for the as needed use of nicotine nasal spray to control withdrawal symptoms, possibly in combination with other medications with longer acting effects. Received: 18 February 1998/Final version: 1 May 1998     

Characterization of tobacco withdrawal symptoms: transdermal nicotine reduces hunger and weight gain

The accurate assessment of both tobacco withdrawal and the impact of the nicotine patch on withdrawal may be compromised by attrition of subjects, or by subjects smoking during withdrawal. To reduce these occurrences, 211 participants were provided with intensive cessation counseling while trying to quit smoking with either nicotine (21 mg) or placebo transdermal patches. Subject attrition was low, with 80.5% of participants continuing through the 5-week study period. Abstinence rates were also high over this period (75% and 61% in active and placebo groups, respectively). In this multisite, double-blind trial, withdrawal severity was assessed using a nine-item daily self-report questionnaire, and abstinence was confirmed via CO monitoring. Abrupt smoking cessation increased multiple tobacco withdrawal symptoms/signs including craving for cigarettes, irritability, anxiety, appetite, sleep disruption, difficulty concentrating, restlessness, depression, and impatience. Treatment with transdermal nicotine reduced craving for cigarettes, anxiety, irritability, and appetite, as well as weight gain (1.85 versus 2.88 kg mean gain over 4 weeks in active and placebo groups, respectively). Received: 29 June 1995 / Final version: 22 April 1996     

Behavioral manifestations of the nicotine abstinence syndrome in the rat: peripheral versus central mechanisms

The nicotine abstinence syndrome was studied in the rat utilizing a modified rating scale of the opiate abstinence syndrome. Rats were infused with 10.27 mg/kg per day nicotine hydrogen tartrate for 7 days via subcutaneous minipumps. The behavior of each animal was observed before, during and after termination of the nicotine infusion. The abstinence signs in the withdrawal sessions included gasps, genital licks, ptosis, shakes, teeth chatter, yawns and changes in locomotor activity. Abstinence was induced through surgical removal of the pump or through administration of a nicotinic receptor antagonist, acting either centrally and peripherally (mecamylamine 1 mg/kg SC) or peripherally only (chlorisondamine 1 mg/kg SC). Statistical evaluation revealed a significant increase in overall abstinence signs both at 16 (P < 0.05) and 40 h (P < 0.01) after termination of the nicotine infusion, as compared to the number of signs in the nicotine treated animals’ baseline sessions and to the number of signs in control animals (P < 0.05). There was also a significant reduction in locomotor activity during both withdrawal sessions. Animals injected with mecamylamine or chlorisondamine displayed a larger increase in the abstinence score (P < 0.001) than the spontaneously abstinent animals. Acute administration of different doses of nicotine or of the peripherally acting nicotinic receptor agonist tetramethylammonium (0.8 mg/kg SC) reversed the behavioral nicotine abstinence syndrome. Our results show that a nicotine abstinence syndrome can be elicited in rats on a chronic nicotine regimen either by acute withdrawal of nicotine or by the administration of nicotinic receptor antagonists and that peripheral nicotinic receptors may contribute significantly to the overall withdrawal reaction. Received: 21 March 1996/Final version: 30 September 1996     

Effects of smoking abstinence on adult smokers with and without attention deficit hyperactivity disorder: results of a preliminary study

Rationale Individuals with attention deficit hyperactivity disorder (ADHD) smoke at higher rates than the general population; however, little is known about the mechanisms underlying this comorbidity. Objective This study evaluated the effects of overnight abstinence on withdrawal symptoms and cognitive performance in adult smokers with and without ADHD. Materials and methods Individuals smoking ≥15 cigarettes per day were recruited from the community and underwent an evaluation to establish a diagnosis of ADHD (n = 12) or not (n = 14). Withdrawal symptoms, mood, craving, cognitive performance, and smoking cue reactivity were measured during two laboratory sessions—in a ‘Satiated’ condition participants smoked up to and during the session while in an ‘Abstinent’ condition, participants were required to be smoking abstinent overnight and remain abstinent during the session. Results The effects of abstinence on ADHD and non-ADHD smokers did not differ for withdrawal symptom severity, mood, craving or cue reactivity. Significant Group × Condition interactions were observed for measures of attention and response inhibition on the Conners’ CPT. For reaction time (RT) variability and errors of commission, the ADHD group exhibited greater decrements in performance after overnight abstinence compared to the non-ADHD group. The effects of abstinence on other cognitive measures (e.g., rapid visual information processing task, cued Go/No-Go task) did not differ between the two groups. Conclusion This preliminary study is the first to systematically evaluate the effects of acute smoking abstinence in adult smokers diagnosed with ADHD. Individuals with the disorder may smoke at higher rates due to greater worsening of attention and response inhibition after abstinence.     

Mecamylamine does not precipitate withdrawal in cigarette smokers

Mecamylamine is an antihypertensive that acts via nicotinic antagonism and has been suggested as an aid in smoking cessation. Nicotine dependent patients may not accept mecamylamine if it precipitates withdrawal, as it does in nicotine dependent rats. This study examined mecamylamine’s effects using procedures designed to measure precipitated withdrawal symptoms in humans. Ten cigarette smokers (mean of 37.5 cigarettes/day) and ten non tobacco-using subjects participated in three 6-h sessions. After a 2-h baseline period in which smokers smoked one cigarette every 30 min, oral mecamylamine (0, 10, or 20 mg randomly ordered across sessions) was administered (double-blind). No smoking was allowed for the remainder of the session. Mecamylamine reduced blood pressure and increased heart rate relative to placebo in both the smokers and the non-tobacco users. No reliable direct subjective effects of mecamylamine were observed. Smokers’ subjective reports of cigarette craving and tobacco withdrawal increased, and DSST performance was disrupted over the last 4 h of each session. Effects were independent of dose (placebo versus active). These results suggest that up to 20 mg mecamylamine will not precipitate nicotine withdrawal and that this medication would be acceptable for use in smoking cessation. Received: 20 April 1996/Final version: 3 June 1996     

A quantitative analysis of subjective,cognitive, and physiological manifestations of the acute tobacco abstinence syndrome

Rationale

Previous studies have documented the existence of signs and symptoms of the acute tobacco abstinence syndrome; however, less attention has been paid to quantifying the magnitude of these effects.

Objective

The present study quantified the relative magnitude of subjective, cognitive, and physiological manifestations of acute tobacco abstinence.

Method

Smokers (N = 203, ≥ 15 cig/day) attended two counterbalanced laboratory sessions, one following 12-h of abstinence and the other following ad-lib smoking. At both sessions, they completed an extensive battery of self-report measures (withdrawal, affect, hunger, craving, subjective attentional bias towards smoking cues), physiological assessments (heart rate, blood pressure, brain EEG), and cognitive performance tasks (psychomotor processing, sustained attention, objective attentional bias).

Results

Abstinence effects were largest for craving, subjective attentional bias, negative affect, overall withdrawal severity, concentration difficulty, hunger, and heart rate. Effects were moderate for positive affect and EEG power. Effects were small, but reliable, for psychomotor speed, sustained attention, and somatic symptoms. Effects on performance-based indices of attentional bias towards smoking-related cues were small and reliable for some indices but not others. Effects were small and inconsistent for blood pressure and EEG frequency. Variation in internal consistency accounted for 33% of the variation in abstinence effect sizes across measures.

Conclusions

There was a wide range of effect sizes both across and within domains, indicating that the acute tobacco abstinence syndrome is not a monotonic phenomenon. These findings may be indicative of the relative magnitudes of signs and symptoms that the average smoker may exhibit during acute abstinence.     

Anxiety and depressive symptoms and affective patterns of tobacco withdrawal

Background

The complex concordance and discordance across and within anxiety and depressive symptoms complicates understanding of the relation between emotional symptoms and manifestations of tobacco withdrawal. The goal of this study was to parse the broad variation in anxiety and depressive symptoms into conceptually discrete components and explore their relative predictive influence on affective patterns of acute tobacco withdrawal.

Methods

We employed a within-participant experimentally manipulated tobacco abstinence design involving: (i) a baseline visit at which past-week depression and anxiety symptoms were assessed and (ii) two counterbalanced experimental visits—one after ad lib smoking and one after 16-h of tobacco abstinence—at which state affect was assessed. Participants were community-dwelling adults (N = 187) smoking 10+ cig/day for at least two years without an active mood disorder.

Results

Anxiety-related general distress symptoms (e.g., tension, nervousness) predicted greater abstinence-induced increases in various negative affective states but not changes in positive affect (βs .17–.33). Depression-related general distress symptoms (e.g., sadness, worthlessness) predicted greater abstinence-induced increases in acute depressed affect only (βs .24–.25). Anhedonic symptoms (e.g., diminished interest, lack of pleasure) predicted larger abstinence-induced decreases in acute positive affect only (βs .17–.20). Anxious Arousal symptoms (e.g., shakiness, heart racing) predicted larger abstinence-induced increases in fatigue and depressive affect (βs .15–.24).

Conclusion

Different components of anxiety and depressive symptoms are associated with unique affective patterns of acute tobacco withdrawal. These results provide insight into the affective mechanisms underlying tobacco dependence and could inform smoking cessation treatment approaches tailored to individuals with emotional distress.     

The nitric oxide synthesis inhibitor nitro-L-arginine (L-NNA) attenuates nicotine abstinence syndrome in the rat

Nitric oxide synthesis contributes to opiate tolerance and dependence. Nicotine dependence and abstinence syndrome in the rat appear to involve opiate mechanisms. Therefore, it was postulated that nitric oxide synthase (NOS) activity might be essential for the expression of nicotine abstinence syndrome. Twenty-one rats were rendered dependent by SC infusion of 9 mg/kg per day nicotine tartrate via Alzet osmotic minipump. Rats were pretreated SC with vehicle alone, or with 18 or 30 mg/kg of the NOS inhibitor L-NNA (nitro-L-arginine). Thirty minutes later, rats were challenged by 1 mg/kg of the nicotinic antagonist mecamylamine SC and observed for 30 additional minutes. Rats pretreated with vehicle displayed a total of 68.7 ± 8.0 mecamylamine-precipitated abstinence signs (mean ± SEM), while those receiving 18 or 30 mg/kg L-NNA had 12.7 ± 2.0 and 5.1 ± 1.7 signs, respectively. All three groups differed significantly from one another according to Dunn’s post-hoc procedure. Rats pretreated with L-NNA combined with an excess of the NOS substrate L-arginine had significantly more mecamylamine-precipitated abstinence signs than rats receiving L-NNA combined with D-arginine. Also, D-NNA, which does not selectively bind to NOS, was significantly less effective than L-NNA in preventing mecamylamine-precipitated abstinence syndrome. Additional studies determined the effect of L-NNA on spontaneous nicotine abstinence syndrome. Rats were assessed for abstinence signs at 17 and 20 h after termination of nicotine infusion. They received injections of 9, 18, or 30 mg/kg L-NNA SC or vehicle alone immediately before the 20-h observation; all rats were observed for 30 min. Signs at 20 h (post-injection) as a percentage of signs at 17 h (pre-injection) declined significantly as a function of L-NNA dose. Once again, this effect was attenuated significantly more by co-administration of L-arginine than by D-arginine. The overall pattern of results suggests that nitric oxide synthesis is critical to the expression of nicotine abstinence syndrome. Received: 20 January 1998/Final version: 8 April 1998     

Associations between Cloninger's temperament dimensions and acute tobacco withdrawal

This study examined associations between three temperament dimensions measured by the Temperament and Character Inventory-125 [Cloninger, C.R. (1992). The Temperament and Character Inventory-125 (TCI-125; Version 1.)] and tobacco abstinence effects. Smokers (N=203, >/= 15 cigarettes/day) attended two laboratory sessions, one following 12 h of abstinence and the other following ad libitum smoking (order counterbalanced). Participants completed measures of withdrawal symptoms, cigarette urges, and affect. Smokers high in Novelty Seeking reported greater abstinence-induced increases in several nicotine withdrawal symptoms, negative affect, and cigarette craving. Smokers high in Harm Avoidance reported greater abstinence-induced increases in negative affect and urges to smoke to relieve distress. Reward Dependence was not associated with abstinence effects. Novelty Seeking and Harm Avoidance showed independent predictive associations with negative affect and urges, and their associations with abstinence effects persisted when controlling for FTND scores. Smokers with different temperaments display different patterns of acute tobacco withdrawal, and may benefit from treatments matched to their particular abstinence profile.     

Attention-deficit/hyperactivity disorder (ADHD) symptoms, craving to smoke, and tobacco withdrawal symptoms in adult smokers with ADHD

Background

Tobacco withdrawal symptoms may be confounded with attention-deficit/hyperactivity disorder (ADHD) symptoms among smokers with ADHD.

Objective

(1) To assess overlap between ADHD symptoms and tobacco/nicotine withdrawal symptoms and craving; (2) to assess the relationship between craving or withdrawal symptoms and the effect of osmotic-release oral system methylphenidate (OROS-MPH) on ADHD symptoms; (3) to assess the association of ADHD symptoms, craving, and withdrawal symptoms with abstinence.

Methods

Secondary analysis of a randomized, placebo controlled smoking cessation trial assessing the efficacy of OROS-MPH taken in addition to nicotine patch among individuals with ADHD. ADHD symptoms, withdrawal symptoms, and craving were assessed at baseline and 2, 4 and 6 weeks after a target quit day.

Results

Withdrawal symptoms and craving showed limited and modest overlap with ADHD symptoms prior to abstinence but more extensive and stronger correlation after quit day. Compared to placebo, OROS-MPH reduced ADHD symptoms; this effect was attenuated by controlling for withdrawal symptoms, but not by craving. Craving, but not ADHD symptoms and withdrawal symptoms, was associated with abstinence during the trial.

Conclusion

When treating smokers with ADHD (1) craving, rather than tobacco withdrawal symptoms or ADHD symptoms may be the more effective therapeutic smoking cessation targets; (2) careful distinction of craving, withdrawal symptoms, and ADHD symptoms when assessing withdrawal phenomena is needed.     

Cotinine: effects with and without nicotine

 The purpose of this study was to examine the effects of the metabolite of nicotine, cotinine, in comparison to the effects of the nicotine patch, and a combination thereof during cigarette abstinence. More specifically, this study examined the effects of cotinine on physiological measures, subjective measures assessing craving, withdrawal symptoms and mood, and performance measures. A between-subject, 2 × 2 factorial design was used, with the daily administration of a 15-mg nicotine patch (Nicotrol) versus placebo patch as one factor and 80 mg of oral cotinine fumarate versus placebo drug as the other factor. Baseline measures were obtained while the subjects smoked cigarettes on an ad lib basis for 1 week. Subjects (n = 106) were then randomly assigned to one of four treatment conditions and for the next 14 days were required to be abstinent from cigarettes and take the study drugs. Cotinine administration, with or without nicotine patch, produced serum cotinine concentrations 3–4 times higher than during ad lib smoking. Results showed a reduction of self-reported tobacco withdrawal symptoms using the nicotine patch alone. Cotinine alone had no effect on withdrawal symptoms. However, when nicotine patch was combined with cotinine, the beneficial effect of the nicotine patch on withdrawal symptoms was absent. Therefore, cotinine appears to antagonize the effects of nicotine in the alleviation of withdrawal symptoms at concentrations higher than that attained from normal smoking. This effect does not appear to be mediated by changes in nicotine disposition. Received: 27 March 1997/Final version: 14 July 1997     

Tobacco withdrawal symptoms and urges to smoke in pregnant versus non-pregnant smokers

We compared tobacco withdrawal in pregnant and non-pregnant smokers abstaining from smoking for 24h. Female smokers completed an internet-based questionnaire, including the Minnesota Nicotine Withdrawal Scale-Revised (MNWS). They also rated additional withdrawal items and strength of urge to smoke. Consenting women were randomized to either: (i) abstain from smoking for 24h or (ii) smoke as usual. After 24h they rated their withdrawal again. We included a 'smoking as usual' group as we wished to establish that smoking abstinence increased withdrawal symptoms. Two-hundred and seventy-five women completed both the initial and the 24h questionnaire and reported abstaining (n=115, 17% pregnant) or smoking (n=160, 21% pregnant) as requested. Exclusively among abstinent smokers, we compared symptoms for the pregnant and non-pregnant groups. After 24h pregnant women had significantly lower scores than non-pregnant women for the mean MNWS (p=0.004) and for three individual MNWS symptoms (angry, p=0.010; anxious, p=0.048; impatient, p=0.011), with adjustments for baseline cigarette consumption and baseline withdrawal scores. Overall, on the first day of smoking abstinence, pregnant women are likely to report less severe tobacco withdrawal than non-pregnant women.     

Withdrawal from IV cocaine “binges” in rats: ultrasonic distress calls and startle

 Human cocaine abusers report that they experience intense anxiety during withdrawal from chronic use or “binging”. Because the symptoms of cocaine withdrawal are not easily observed, it has been difficult to develop an adequate animal model for cocaine withdrawal that det′ects anxiety-like behavior. The objective of the present study was to examine the effects of continuous access to IV self-administered cocaine on ultrasonic vocalizations (USVs) induced by startling tactile stimuli as a possible animal model for cocaine withdrawal. Five days after implantation of a jugular catheter, rats were placed into self-administration chambers with access to cocaine (0.25 mg/infusion). Once the animal had a stable response rate over 3 days, on a fixed schedule of reinforcement (FR5), they were given unlimited access to cocaine (0.25 mg/infusion) for 48 or 12 h. Subsequently, animals were exposed to 18 air puffs (20 or 10 psi) at 6, 24, 72 h, 7 and 14 days after the “binge”. Rats that self-administered cocaine for 48 h and were subsequently startled with 20 psi stimuli increased the number of automatically recorded ultrasonic distress calls and showed an enhanced startle response at 6 h after the last cocaine infusion when compared to handled controls. Animals that self-administered cocaine for 48 h and were subsequently startled with 10 psi stimuli showed increased USVs and an enhanced startle reflex at both 6 and 24 h after the unlimited access. Animals that self-administered cocaine for 12 h also showed an increase in ultrasonic distress calls and enhanced startle responses to 10 psi tactile stimuli when compared to handled controls. USVs during cocaine withdrawal may be interpreted to reflect affective distress during the first 24 h after the last cocaine infusion of 12 or 48 of continuous access to drug. Received: 7 April 1997/Final version: 8 July 1997     

Naltrexone administration affects ad libitum smoking behavior

Endogenous opioid peptides have been implicated in the reinforcement of smoking and opioid antagonists have been examined to determine their role in smoking behavior. To date, the relationship between smoking behavior and chronic opiate antagonist administration during ad libitum smoking has not been investigated. The purpose of this study was to examine the relationships between naltrexone, an opiate antagonist administered orally, and smoking behavior and mood states during ad libitum smoking. A repeated measures experimental design was used. Normal adult male and female volunteers, admitted to the Clinical Research Center, were randomly assigned to naltrexone-treated (n = 22) or placebo-control (n = 21) groups in a double-blind manner. Day 1 was considered acclimation to the unit and day 2 was baseline, or pre-drug administration. On days 3, 4, and 5, subjects received 50 mg naltrexone or a placebo at 0700 and 1600 hours. Plasma nicotine and expired air carbon monoxide levels were measured daily at 1900 hours. Number of cigarettes smoked, mood states, withdrawal symptomatology and self-reported satisfaction with smoking were also quantified daily. Results indicated that plasma nicotine levels (P = 0.005), number of cigarettes smoked daily (P = 0.003) and self-reported satisfaction with smoking (P = 0.043) were significantly lower among those treated with naltrexone, compared to the placebo-control group. Expired air carbon monoxide levels did not differ between the two groups. In addition, mood states and withdrawal symptoms did not differ between groups. These findings suggest that endogenous opioid peptides influence specific smoking behavior variables. Received: 7 November 1997/ Final version: 7 April 1998     

Comparative analysis of waterpipe and cigarette suppression of abstinence and craving symptoms

This study's objective is to examine the relative effectiveness of cigarettes and waterpipe (WP) in reducing tobacco abstinence symptoms in dual cigarette/WP smokers. Sixty-one dual cigarette/WP smokers participated (mean age±SD 22.0±2.6 year; mean cigarettes/day 22.4±10.1; mean WPs/week 5.2±5.6). After 12-hour abstinence participants completed two smoking sessions (WP or cigarette), while they responded to subjective measures of withdrawal, craving, and nicotine effects administered before smoking and 5, 15, 30 and 45 min thereafter. For both tobacco use methods, scores on measures of withdrawal and craving were high at the beginning of session (i.e., before smoking) and were reduced significantly and comparably during smoking. Analysis of smoking and recovery (post-smoking) phases showed similarity in the way both tobacco use methods suppressed withdrawal and craving, but the recovery of some of these symptoms can be faster with cigarette use. This study is the first to show the ability of WP to suppress abstinence effects comparably to cigarettes, and its potential to thwart cigarette cessation.     

Abstinence symptoms following oral THC administration to humans

Symptoms of dependence and withdrawal after the frequent administration of high doses (210 mg/day) of oral Δ⁹-tetrahydrocannabinol (THC) have been reported, yet little is known about dependence on lower oral THC doses, more relevant to levels attained by smoking marijuana. In a 20-day residential study, male (n = 6) and female (n = 6) marijuana smokers worked on five psychomotor tasks during the day (0915–1700 hours), and in the evening engaged in private or social recreational activities (1700–2330 hours); subjective-effects measures were completed 10 times/day, and a sleep questionnaire was completed each morning. Food and beverages were available ad libitum from 0830 to 2330 hours. Capsules were administered at 1000, 1400, 1800, and 2200 hours. Placebo THC was administered on days 1–3, 8–11, and 16–19. Active THC was administered on days 4–7 (20 mg qid) and on days 12–15 (30 mg qid). Both active doses of THC increased ratings of “High,”“Good Drug Effect,” and “Willingness to Take Dose Again” compared to baseline (days 1–3). THC also increased food intake by 35–45%, and decreased verbal interaction among participants compared to placebo baseline. Tolerance developed to the subjective effects of THC but not to its effects on food intake or social behavior. Abstinence from THC increased ratings of “Anxious,”“Depressed,” and “Irritable,” decreased the reported quantity and quality of sleep, and decreased food intake by 20–30% compared to baseline. These behavioral changes indicate that dependence develops following exposure to lower daily doses of THC than have been previously studied, suggesting that the alleviation of abstinence symptoms may contribute to the maintenance of daily marijuana use. Received: 13 April 1998/Final version: 1 July 1998     

Buprenorphine and naloxone combinations: the effects of three dose ratios in morphine-stabilized, opiate-dependent volunteers

Sublingual buprenorphine is a promising new treatment for opiate dependence, but its opioid agonist effects pose a risk for parenteral abuse. A formulation combining buprenorphine with the opiate antagonist naloxone could discourage such abuse. The effects of three intravenous (IV) buprenorphine and naloxone combinations on agonist effects and withdrawal signs and symptoms were examined in 12 opiate-dependent subjects. Following stabilization on a daily dose of 60 mg morphine intramuscularly, subjects were challenged with IV doses of buprenorphine alone (2 mg) or in combination with naloxone in ratios of 2:1, 4:1, and 8:1 (1, 0.5, or 0.25 mg naloxone), morphine alone (15 mg) or placebo. Buprenorphine alone did not precipitate withdrawal and had agonist effects similar to morphine. A naloxone dose-dependent increase in opiate withdrawal signs and symptoms and a decrease in opioid agonist effects occurred after all drug combinations. Buprenorphine with naloxone in ratios of 2:1 and 4:1 produced moderate to high increases in global opiate withdrawal, bad drug effect, and sickness. These dose ratios also decreased the pleasurable effects and estimated street value of buprenorphine, thereby suggesting a low abuse liability. The dose ratio of 8:1 produced only mild withdrawal symptoms. Dose combinations at 2:1 and 4:1 ratios may be useful in treating opiate dependence. Received: 9 February 1998/Final version: 8 May 1998     

Nicotine availability from Eclipse tobacco-heating cigarette

A cigarette which heats rather than burns tobacco (Premier) was introduced in 1988, but was unacceptable due to unpleasant taste and low nicotine intake. We examined availability of nicotine from a new version (Eclipse), in the same four subjects as our earlier Premier study. Average blood nicotine boosts of 23.7 and 17.8 ng/ml were obtained from smoking a first and second Eclipse. This substantially exceeds intake from Premier (boost 13 ng/ml) and that obtained by heavy smokers from conventional brands (boost 12–15 ng/ml). Eclipse (or similar product) may be the best option for averting Peto’s dire warnings of rising millions of annual smoking deaths in the 2020 s, and its potential for large-scale, long-term switching warrants further study. Received: 24 April 1998/Final version: 28 May 1998     

ADHD medication reduces cotinine levels and withdrawal in smokers with ADHD

Individuals with ADHD may self-medicate with nicotine, the main psychoactive ingredient in tobacco smoke, in order to reduce symptoms and negative moods associated with ADHD. ADHD medication (e.g., methylphenidate and atomoxetine) may mimic some of the effects of nicotine and may aid smoking cessation in smokers with ADHD. The present study examined if ADHD medication reduces smoking and withdrawal in non-treatment seeking smokers with ADHD. Fifteen adult smokers with ADHD participated in the study, which consisted of an experimental phase and field monitoring phase to examine the acute and extended effects, respectively, of ADHD medication. During the experimental phase, smokers were asked to complete a Continuous Performance Task (CPT) and the Shiffman-Jarvik smoking withdrawal questionnaire during the following four conditions: (1) ADHD medication + cigarette smoking, (2) ADHD medication + overnight abstinence, (3) placebo + cigarette smoking, and (4) placebo + overnight abstinence. During the field monitoring phase, participants were asked to provide salivary cotinine samples and complete electronic diaries about smoking, smoking urge, ADHD symptoms, and stress in everyday life for two days on ADHD medication and for two days on placebo. Results of the experimental phase showed that ADHD medication improved task performance on the CPT and reduced withdrawal during overnight abstinence. During the field monitoring phase, ADHD medication reduced salivary cotinine levels compared to placebo. In addition, the electronic diary revealed that ADHD medication improved difficulty concentrating during no smoking events and stress. The findings of the present study suggest that, along with other strategies, ADHD medication may be used to aid smoking withdrawal and cessation in smokers with ADHD.     

Trazodone and valproate in patients discontinuing long-term benzodiazepine therapy: effects on withdrawal symptoms and taper outcome

Recent uncontrolled research suggested that trazodone and sodium valproate may be helpful in benzodiazepine (BZ) discontinuation. We therefore undertook a double-blind study to assess whether trazodone and valproate, as compared to placebo, would attenuate withdrawal and facilitate discontinuation in BZ-dependent patients with a minimum of 1 year daily BZ use. Seventy-eight patients, taking a mean dose of 19 ± 17 mg/day of diazepam (or its equivalent), were stabilized for several weeks on their BZ (16 diazepam, 25 lorazepam, 37 alprazolam) and then for 1–2 weeks, pretreated with trazodone, sodium valproate or placebo before being tapered at 25% per week. All treatments were continued for 5 weeks post-taper. BZ-free status was assessed after 5 and 12 weeks post-taper. Neither trazodone nor valproate had any significant effect on withdrawal severity. Peak physician withdrawal checklist change from baseline to peak severity was 16.4 for trazodone, 18.04 sodium valproate and 18.24 placebo (F = 0.10; NS). Taper success rates were significantly effected by both active agents at the 5-week, but not 12-week, assessment. At 5 weeks post-taper, 79% of sodium valproate and 67% of trazodone, but only 31% of placebo patients were BZ-free (χ² = 7.34; df 2; P < 0.03). Major adverse events for trazodone were sedation and dry mouth, and for valproate, diarrhea, nausea and headaches. Received: 27 March 1997/Final version: 9 June 1998