Psychopharmacology (2002) 164:177–187 DOI 10.1007/s00213-002-1176-1
ORIGINAL INVESTIGATION
Vincenzo Teneggi · Stephen T. Tiffany · Lisa Squassante · Stefano Milleri · Luigi Ziviani · Alan Bye
Smokers deprived of cigarettes for 72 h: effect of nicotine patches on craving and withdrawal Received: 23 January 2002 / Accepted: 17 June 2002 / Published online: 27 August 2002 Springer-Verlag 2002
Abstract Rationale: Research on the effects of nicotine abstinence and nicotine replacement has not provided consistent information about the impact of replacement therapies on tobacco withdrawal and craving. Objective: This study investigated craving and withdrawal symptoms over a 72-h period of abstinence from cigarettes. Methods: Twenty-four healthy volunteers, not intending to quit smoking, were housed in an experimental unit during three 72-h conditions, consisting of either free smoking, enforced smoking cessation with nicotine replacement therapy (NRT) patches, or enforced smoking cessation with placebo patches. The conditions were adhered to using a randomized crossover design, each separated by at least 10 days of washout. Patches, administered in a double-blind fashion, were given as nicotine (21 mg/24 h) and placebo every 24 h. Selfreported cigarette craving and withdrawal were assessed using multi-item scales at fixed intervals over each condition period. Urinary and plasma cortisol levels were also assayed at fixed intervals over each period. Results: Craving intensity was significantly lower with free smoke than with placebo and with NRT patches than with placebo. No difference in craving levels was found between those who smoked or those who had NRT patches. Withdrawal symptoms were significantly lower with free smoke than with either placebo or NRT patches, but there was no difference in levels of withdrawal between those on NRT patches and those on placebo. During the placebo and NRT patch periods, craving intensity displayed a circadian rhythm, with craving levels lowest in the morning and peaking in the evening. Nicotine delivered via the patch had no impact on these V. Teneggi ()) · L. Squassante · S. Milleri · L. Ziviani · A. Bye GlaxoSmithKline SpA, Medicine Research Centre, Via A. Fleming N 4, 37135 Verona, Italy e-mail:
[email protected] Tel.: +39-045-9218520 Fax: +39-045-9218191 S.T. Tiffany Department of Psychological Science, Purdue University, West Lafayette, Ind., USA
circadian variations in craving. There was no evidence of systematic temporal variations in craving levels during the free smoking period. Conclusions: The data suggested that craving and withdrawal symptoms may be sustained by different physiological pathways, and that only selected components of cigarette craving are influenced by NRT. Keywords Craving · Nicotine patch · Smoking withdrawal symptoms · Pulse rate · Cortisol
Introduction The 1988 Surgeon General’s Report claimed that nicotine addiction was responsible for the maintenance of smoking behavior and the general failure of treatment interventions for smoking (Paten and Martin 1996). Smokers commonly attribute their inability to quit or maintain abstinence to distressing withdrawal symptoms and craving (Paten and Martin 1996). The Diagnostic and Statistical Manual (DSM-IV) of the American Psychiatric Association (1994) identified eight signs and symptoms as indicators of the nicotine-withdrawal syndrome. These included anxiety, difficulty concentrating, restlessness, decreased heart rate, increased appetite or weight gain, irritability, frustration or anger, insomnia, and dysphoric or depressed mood. Studies of unaided quitters have found that, at 1–2 days post-quitting, 70–85% report withdrawal symptoms (Gritz et al. 1991; Breslau et al. 1992). The various withdrawal signs/symptoms appear 6–12 h after smoking cessation and most of these symptoms can last for 3–4 weeks (Hughes 1992). Previous versions of DSM had included craving as a feature of withdrawal, but this symptom was excluded in DSM-IV primarily because craving and withdrawal may not have comparable profiles over the course of abstinence (American Psychiatric Association 1994; Paten and Martin 1996). Although there is some disagreement about whether or not craving is a component of nicotine withdrawal, there is little dispute that
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craving is a prominent characteristic of nicotine dependence (Gritz et al. 1991; Breslau et al. 1992; UNDCP and WHO 1992; Paten and Martin 1996). Craving emerges early in the smoking history of cigarette smokers (Corrigall et al. 2002) and regular cigarette smokers report high levels of craving even while actively smoking (Tiffany and Drobes 1991). Craving can increase in intensity after 1 h of cigarette deprivation and may reach peak levels within 6–24 h of abstinence (Maude-Griffin and Tiffany 1996). Individuals who have quit smoking can continue to experience craving 6 months or more after initiating abstinence (Hughes et al. 1994). Although nicotine deprivation is the primary source of the nicotine withdrawal syndrome, craving can be activated by stimulus conditions in addition to deprivation. For example, alcohol intoxication, negative affective states, and environmental cues, associated with previous episodes of smoking, are all potent triggers of craving (Maude-Griffin and Tiffany 1996; Burton and Tiffany 1997; Carter and Tiffany 1999). These considerations suggest that craving and nicotine withdrawal may be controlled by separate processes. This possibility is consistent with research showing that craving but not withdrawal is prospectively associated with successful smoking cessation or maintained abstinence (Curry and Bride 1994; Kenford et al. 1994; Killen and Fortman 1997). Furthermore, research on nicotine replacement in abstinent smokers suggests that these treatments can have a differential impact on withdrawal and craving symptoms (Leischow et al. 1997; Tiffany et al. 2000). Several factors have impeded the generation of definitive conclusions about the effect of nicotine replacement on craving and withdrawal symptoms. First, much of this research has been conducted in the context of smoking treatment programs (Hughes et al. 1984; Schneider et al. 1984; Schneider and Jarvik 1984; The Transdermal Nicotine Study Group 1991). Consequently, the impact of nicotine replacement on withdrawal and craving is generally confounded with differential rates of abstinence across nicotine and placebo conditions. Second, assessments of withdrawal and craving are generally collected too infrequently to provide comprehensive profiles of symptom changes across relatively brief periods. More frequent assessments could be particularly revealing in light of evidence that levels of cigarette craving may vary systematically over the course of the day, with craving peaking in the late afternoon and evening hours (Glassman et al. 1984; Hughes et al. 1984; Schneider and Jarvik 1984; Fagerstrm et al. 1993). However, there has been limited research on the extent to which nicotine replacement might affect diurnal variation in cigarette craving or nicotine withdrawal (Schneider and Jarvik 1984; Fagerstrm et al. 1993). Third, assessment of craving itself has generally been limited in most nicotinereplacement research, with craving levels evaluated with single-item questionnaires of unknown reliability and validity. Finally, few laboratory-based studies of nicotine replacement have included a control condition in which smokers were allowed to smoke ad lib. Given that craving
levels tend to be moderately high in non-abstinent smokers (Tiffany and Drobes 1991), the use of a nonabstinent condition can provide important baseline information about the temporal dynamics of craving and withdrawal when smokers are not deprived of cigarettes. The present research examined the profiles of changes of craving levels and withdrawal symptoms over the course of a 72-h period in which smokers were instructed to smoke freely or remain abstinent from cigarettes. During the abstinence conditions, smokers wore either a placebo patch or an active nicotine patch. All smokers participated in each condition, and the 72-h treatment periods were conducted in an experimentally controlled setting. The participants rated withdrawal symptoms and craving at regular intervals throughout each treatment period with Italian versions of multi-item instruments that have been used extensively in previous research on craving (The Questionnaire on Smoking Urges – Brief, QSU-brief; Cox et al. 2001) and withdrawal [The Smoker Complaint Scale, SCS; Schneider (1994) and The Smoking Withdrawal Questionnaire; SWQ, Shiffman and Jarvik 1976; Schneider 1994]. (Italian versions available upon request from the corresponding author). Pulse rate and blood pressure were also assessed at regular intervals throughout each treatment period. Although there is consistent evidence of pulse rate reductions during cigarette abstinence, the impact of abstinence on blood pressure changes is less certain (Schneider and Jarvik 1984). These different outcomes might be due to variations in time of measurement (i.e., different days or time of the day), to variations in numbers of daily assessments or differences in the type of subjects studied. The few studies that have assessed the effect of acute cigarette withdrawal on cortisol levels have produced conflicting results (Frederick et al. 1998; Wallace et al. 1998; Veldhuis 2000). Some short-term abstinence (less than 24 h) studies have shown either no effect or increased cortisol levels. Other studies have shown reductions in cortisol levels, which appear to be related to the degree of distress experienced during the early quitting period. These disparate outcomes might be due to variations in normal ranges of cortisol levels, the different sources of cortisol samples (i.e., plasma or urine), or time of measurement (i.e., different days or time of the day), or even differences in the type of subjects studied. The present investigation attempted to address the methodological limitations of previous research on abstinence and cortisol levels. Plasma and urine cortisol levels were assayed across the treatment periods. Plasma levels were assessed at the same time points as for craving and withdrawal symptoms. Urine levels were assessed daily with two 12-h urine aliquots.
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Materials and methods Design This was a double-blind (for the nicotine and placebo patch sessions), randomized, three-period, crossover study with 24 subjects enrolled. Each subject participated in three different 72-h conditions: (1) nicotine replacement therapy (NRT) patch administration every 24 h for four consecutive days, quitting smoking abruptly on the morning after the first patch application; (2) placebo patch administration every 24 h for four consecutive days, quitting smoking abruptly on the morning after the first patch application; and (3) free smoke for four consecutive days. There was a wash out of at least 10 days between each study period. Subjects attended the Clinical Pharmacology Unit of GlaxoSmithKline, Verona (Italy), on five occasions: a pre-study screening visit, three 72-h study periods, and a post-study follow-up visit. The total duration of a subject’s participation was approximately 8 weeks. Subjects entered the research facility by 1900 hours on the evening before the start of clinical and pharmacodynamic evaluations. Subjects A total of 24 healthy volunteers, 20 males and 4 females, were recruited from the panel of volunteers of the Clinical Pharmacology Unit. All these subjects were not intending to quit smoking and were paid for their participation. Inclusion criteria established that subjects were at least 18 years old; smoked an average of 15 cigarettes or more a day for the past year; had Fagerstrm tolerance questionnaire (FTQ) scores of at least 7; were healthy as determined by physical, neurological and psychiatric examination, medical history, electrocardiogram (ECG) and laboratory studies; were able to read, comprehend, and write Italian; and had signed a written informed consent prior to study participation. Exclusion criteria included any history of drug or skin allergies, drug or alcohol abuse, use of long-term medication, use of any drug within the previous 4 weeks, current use of any NRT, alcohol intake during the 2 days prior to the study or illness at the time of the study, and previous participation in any clinical study during the 6 months before the first study day. Regulatory and ethics committee approval was obtained before the start of the study, which was conducted in accordance with the Declaration of Helsinki. Treatments Drug medications were NRT, given as a nicotine patch (Nicotinell) or drug-free patches, administered every 24 h. NRT patches were of the Italian marketed product Nicotinell [TTS 30, by Novartis (30 cm2, containing a total 52.5 mg nicotine and delivering approximately 21 mg/24 h)]. This is roughly the amount of nicotine absorbed by a smoker smoking at least 15 cigarettes per day. NRT placebo (drug free) patches were manufactured by Lohmann Therapie-Systeme (LTS) according to GSK specification. Procedure Subjects who met inclusion criteria were admitted to the unit on the evening preceding day 1 and remained until 6 h after the end of each study period on day 4. During each of the study periods, subjects had to refrain from alcohol, consumption of coffee (except for breakfast and lunch), any prescribed concomitant medication and any over-the-counter preparations, strenuous exercise, and all recreational drugs (“drugs-of-abuse” urine tests were performed during the study to monitor compliance with this restriction). Nicotine and placebo patches were applied at 2300 hours on the evening preceding day 1, then replaced at the same time on days 1, 2, and 3. Patches were supplied into a daily envelope within a study-period treatment pack for each subject. For blinding and
protective purposes, both NRT and NRT placebo patches were covered by the application of an overlay patch manufactured by LTS. In order to maintain the blinding and to reduce the hypothetical risk of detecting nicotine, seeing or smelling, the study patches were applied by an independent administrator on the subjects’ backs and then immediately covered by the overlay patch. Subjects that received NRT or placebo patches quit smoking around 0730 hours on the morning of day 1, around 8.5 h after the first patch administration, as nicotine patches required 2–8 h to reach adequate nicotine blood levels. Measurements and evaluations Measures were collected at various time intervals throughout each treatment period with time zero (0) at 0800 hours, which corresponded to the beginning of the enforced abstinence (30 min after the subject’s last cigarette). Other time points were: –0.5 h (0730 hours), 3 h (1100 hours), 6 h (1400 hours), 12 h (2000 hours), 24 h (0800 hours), 27 h (1100 hours), 30 h (1400 hours), 36 h (2000 hours), 48 h (0800 hours), 51 h (1100 hours), 54 h (1400 hours), 60 h (2000 hours), and 72 h (0800 hours). Self-report questionnaires were administered at 0, 3, 6, 12, 24, 30, 36, 48, 54, 60, and 72 h to evaluate craving and withdrawal symptoms. The QSU-brief, which assessed craving/urge to smoke, consisted of 10 items scored on a likert scale of 1 (I strongly disagree) to 7 (I strongly agree). The average total score ranged from 1 to 7. The SWQ, which assessed withdrawal symptoms, consisted of 25 items scored on a likert scale of 1 (very definitely) to 7 (very definitely not). The questionnaire yielded five factors with scores ranging from 1 to 7. Higher scores indicated lower levels of withdrawal. The SCS, which also assessed withdrawal symptoms, consisted of 20 items scored on a likert scale of 1 (very definitely not) to 7 (very definitely). The sum total score ranged from 20 to 140. Higher scores represented the presence of higher levels of withdrawal symptoms. Pulse rate and blood pressure were taken at 0, 6, 24, 30, 48, 54, and 72 h. Plasma samples were collected for cortisol level determination at –0.5, 3, 6, 12, 24, 27, 30, 36, 48, 51, 54, 60, and 72 h. Urine was collected for cortisol analysis over the following time intervals: 0– 12, 12–24, 24–36, 36–48, 48–60, and 60–72 h. Cortisol assays from plasma and urine were performed using a radioimmunoassay (RIA) method [limit of quantification (LOQ) 2 ng/ml]. Saliva samples for nicotine and cotinine levels were collected at 0, 6, 12, 24, 30, 36, 48, 54, 60, and 72 h. Saliva samples were analyzed for nicotine and cotinine levels using liquid-chromatography mass/mass spectrometric (LC-MS/MS) assay at LOQ of 5 ng/ml, using a 1-ml sample. Breath carbon monoxide (CO) measurements were performed at 0, 6, 12, 24, 30, 36, 48, 54, 60, and 72 h using EC50 Micro III Smokerlyzer (Bedfont Instruments, Kent, UK). Data analysis Total and factor scores of craving and withdrawal symptoms were summarized for each subject using the weighted mean over each 72-h treatment period. This was calculated as the area under the measurement–time curve divided by the time over which the measurements were taken, using the linear trapezoidal method. The weighted means of each total score and factor were then analyzed by means of analysis of variance (ANOVA) taking into account subjects, periods and treatments. Estimates of least-square (LS) mean values were evaluated for each treatment. Treatment differences were estimated on a pair-wise basis. Due to the exploratory nature of the analysis, no correction for multiplicity of tests was performed. Total scores of craving and withdrawal symptoms were also analyzed as a function of time of day and investigated to capture any circadian trends (as quadratic component) across 24-h periods. Blood-pressure and heart-rate measurements were also summarized and analyzed for each subject using
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