Psychopharmacology(1991) 104:496-504 0033315891001524
Psychopharmacology © Springer-Verlag 1991
Signs and symptoms from nicotine gum abstinence Dorothy K. Hatsukami 1, Kelli Skoog 1, Marguerite Huber 1, and John Hughes 2 1 Universityof Minnesota, Department of Psychiatry,Box 392 Mayo, Minneapolis, MN 55455, USA 2 Universityof Vermont, Department of Psychiatry,College of Medicine, Burlington,VT 65405, USA Received June 19, 1990 / Final version November 12, 1990
Abstract. This study examined and compared withdrawal signs and symptoms from cessation of 0, 2 and 4 mg nicotine gum. In addition, a comparison was made between nicotine gum versus cigarette withdrawal symptoms. Smokers first underwent cigarette deprivation for 4 days and then were randomly assigned to 0 (N= 16), 2 (N= 25), and 4 (N= 21) mg gum. They were asked to chew the gum for 1 month and then to undergo a 4-day nicotine gum deprivation period. The results showed a number of significant changes occurring after deprivation from 4 mg gum, one change from 2 mg gum, and no changes from 0 mg gum. There were no significant differences in severity of withdrawal among the various doses of nicotine gum. There were more severe symptoms of withdrawal from cigarette as opposed to 4 mg nicotine gum deprivation. Key words" Nicotine gum
Cigarette - Withdrawal
Significant signs and symptoms of withdrawal have been found after cigarette and smokeless tobacco deprivation (USPHS 1988; Hughes et al. 1989a). The question arises as to whether these signs and symptoms are due exclusively to the effects of nicotine or from other constituents of smoke and tobacco exposure. There are three ways to answer this question. One way is to examine whether a nicotine antagonist precipitates withdrawal signs and symptoms. Mecamylamine, a CNS nicotine blocker, has produced equivocal results in its ability to precipitate withdrawal signs and symptoms (Stolerman et al. 1973; Tennant et al. 1984; Nemeth-Coslett et al. 1986). In fact, a recent review reported that mecamylamine may not be a potent blocker of the cholinergic nicotine receptor (Hughes et al. 1989a) Thus, if withdrawal signs and symptoms are associated with cholinergic nicotine receptors, mecamylamine would not be expected to precipitate withdrawal. Offprint requests to. D.K. Hatsukami
Another method to determine whether withdrawal signs and symptoms are due to nicotine is to see whether nicotine can alleviate these signs and symptoms. Several studies have carefully and specifically examined whether nicotine gum can alleviate withdrawal symptoms which are experienced after giving up smoking (Jarvis et al. 1982; Hughes et al. 1984; Schneider et al. 1984; West et al. 1984; Gross and Stitzer 1989). In general, the studies showed that nicotine gum does alleviate some of the symptoms of withdrawal, most notably anxiety, irritability, and decreased concentration, but does not alleviate others, particularly craving. The final way is to examine the changes which occur after deprivation fi'om nicotine alone. Two studies have examined the withdrawal effects after deprivation from 2 mg nicotine gum (West and Russell 1985; Hughes et al. 1986). These studies found signs and symptoms of nicotine withdrawal to be similar to that of tobacco withdrawal. Both studies, however, included only subjects who had used nicotine gum for at least a year or had used for median of 5 months, thus, biasing the sample to those who are behaviorally dependent on the gum. No study has yet examined withdrawal symptoms from nicotine gum in smokers who have never used the gum and who are randomly assigned to different doses of nicotine gum. Furthermore, no study has yet examined withdrawal from 4 mg gum which produces higher levels of nicotine than 2 mg gum. In the present study, we examined and compared withdrawal signs and symptoms from cessation of 0, 2, and 4 mg nicotine gum. We also compared withdrawal symptoms from nicotine gum cessation versus cigarette cessation. Smokers who were motivated to quit smoking first underwent cigarette deprivation for 4 days and then were randomly assigned to one of three doses of nicotine gum 0, 2 or 4 mg. They were asked to chew the gum for 1 month and then to stop chewing gum for a period of 4 days. This study thus provides further empirical information regarding the extent to which signs and symptoms of tobacco withdrawal can be attributed to the nicotine itself and whether withdrawal from nicotine
497 g u m is dose related. A d d i t i o n a l l y , this s t u d y also provides a direct c o m p a r i s o n o f the w i t h d r a w a l f r o m signs a n d s y m p t o m s f r o m cigarettes a n d n i c o t i n e g u m e m p l o y i n g a w i t h i n - s u b j e c t design. F i n a l l y , the results f r o m this study will have clinical utility in d e t e r m i n i n g to w h a t extent s m o k e r s m a y b e c o m e physically d e p e n d e n t o n the gum.
Materials and methods
Subjects. Subjects were adult smokers recruited by newspaper advertisements. Subjects were recruited if they smoked at least a pack of cigarettes/day, were motivated to quit smoking (rated > 7 on an analogue scale ranging from 0 to 10 inquiring on the subjects motivation to quit), and had never used nicotine gum. All subjects also fulfilled DSM-III criteria for tobacco dependence (i.e., use tobacco for 1 month plus prior failure to stop smoking, tobacco withdrawal symptoms, or use despite smoking aggravated illness) and a past history of tobacco withdrawal syndrome. Subjects were excluded from the study if they had medical contraindications to nicotine gum, were presently or planned to be pregnant, had a history of alcohol or drug abuse, past and current psychiatric diagnoses, or were taking psychoactive medications. Informed consent was obtained from all subjects prior to acceptance into the study. Procedure. Subjects were involved in the study for a total of 6 weeks. In week 1, subjects were tested for signs and symptoms of cigarette withdrawal. In weeks 2-5, subjects were asked to chew one of three doses of nicotine gum. In week 6, subjects were tested for signs and symptoms of nicotine gum withdrawal. During the first week, subjects smoked their usual number and brand of cigarettes for 2 days and then underwent a 4-day cigarette deprivation period. Subjects attended five individual late afternoon sessions of 30-45 min duration. At each session, subjects were administered a battery of withdrawal measures (see below) during the 2 days of baseline cigarette smoking (Sunday and Monday) and 3 of the 4 days of cigarette deprivation (Tuesday, Wednesday and Friday). Subjects who were unable to stop smoking (e.g. smoked any cigarettes) during the cigarette deprivation phase of the study were dropped. After the session on Friday of the first week of the study, subjects were randomly assigned in a double-blind fashion to 0, 2 or 4 mg gum. Subject were asked to chew at least six pieces/day of the assigned gum on an ad-lib basis for the next 4 weeks (weeks 2-5). The first two groups (N= 15) were required to chew at least three pieces of nicotine gum/day. However because a significant number chewed only the required pieces of gum, the minimum was raised to six pieces of gum for the subsequent groups of subjects. The number of subjects were equally distributed across doses (0 mg = 4; 2 mg = 6; 4 mg= 5). Subjects were seen briefly each week during this time to facilitate abstinence from smoking and obtain more gum. During each session, the subject was asked about his/her smoking status, gum use, and side effects from the gum. In addition, smoking cessation techniques were discussed as described in "Quit to Win" a self-help treatment manual (Pechacek et al. 1982) given to the subjects during the first week.
During the last week of the study, only subjects who had been able to maintain abstinence from tobacco for the 4 full weeks were allowed to participate. During this week (week 5), subjects were administered the battery of withdrawal measures during 2 days of ad-lib gum chewing (Sunday and Monday). Subjects were asked to quit chewing the nicotine gum after the Monday session and then were tested on the withdrawal battery on 3 of the 4 days during nicotine gum deprivation (Tuesday, Wednesday and Friday). Subjects were required to maintain the same level of alcohol and caffeine use. They were also asked to refrain from caffeine or food intake for 1 h prior to the testing sessions, and not to use any drugs or alcohol at least 8 h before the testing sessions. These measures were employed to minimize the effects of other drugs on the measures of withdrawal. The amount of daily alcohol and caffeine use and time since last use of alcohol and caffeine were measured by self-report Subjects submitted breath samples for carbon monoxide analysis and saliva thiocyanate and cotinine samples to verify smoking abstinence, and (where applicable) salivary samples for cotinine to verify gum use. Subjects were paid $200 if they complied with the experimental procedures. The battery of measures administered to the subjects included physiological, subjective, and behavioral measures. These measures were selected from previous studies we have conducted to determine sensitive and reliable indicators of tobacco withdrawal (Hatsukami et al. 1984; Hughes and Hatsukami 1986). Physiological measures included heart rate and body weight. Subjective measures included a 100 mm visual analog "craving for tobacco" line and a self-rated withdrawal symptoms checklist, found to be a reliable, valid and sensitive measure of tobacco withdrawal symptoms (Hughes and Hatsukami 1986; Hatsukami et al. 1987). This checklist involved rating the following symptoms on a 0-5 scale in which 0 = none and 5 = severe: irritable/angry, anxious/tense, difficulty concentrating, restless, impatient, excessive hunger, somatic symptoms (e.g., sweating, dizziness, and stomach problems), insomnia, increased eating, and drowsiness. A total withdrawal score was obtained by summing the responses (with the exception of the last two items). In addition, the Stanford Sleep Scale, which measures number of awakenings and quality of sleep among other sleep variables (Carskadon et al. 1976), and a 24 h dietary recall form were administered. Behavioral measures included a reaction time and response inhibition task previously shown sensitive to tobacco withdrawal (Hughes et al. 1989b). In this task, subjects were to press a button
Table 1. Demographics and smoking history for the 0, 2, and 4 mg nicotine gum groups 0 mg N=ll
2 mg N=18
4 mg N=19
Sex
Female Male Age Cig/day Nic yield Yrs smoked
5 6 31.9 4-8.9 30.1 4-9.7 0.804-0.20 15.6 4-9.2
9 9 34.6 4-9.4 27.0 4-7.4 0.744-0.22 15.7 4-8.6
10 9 32.5 4-6.8 27.7 4-7.8 0.784-0.39 15.3 4-9.0
Table 2. Saliva cotinine levels (X 4- SE) during cigarette baseline, gum baseline and gum deprivation among subjects assigned to 0, 2 and 4 mg nicotine gum"
Cotinine levels
0 mg
2 mg
4 mg
Cigarette baseline Gum baseline* Gum deprivation
276.71 £ 66.37 (N= 7) 2.71 £ 2.55 (N= 7) 0.434- 0.43 (N=6)
256.87 + 32.16 (N = 15) 84.44 + 34.23 (N = 8) 7.834- 3.26 (N=6)
294.20 4- 38.43 (N= 15) 265.80 4- 58.96 (N = 10) 10.624- 5.52 (N=7)
a Samples were randomly chosen to be sent to the laboratory for analysis. * P_
Psychopharmacology © Springer-Verlag 1991
Signs and symptoms from nicotine gum abstinence Dorothy K. Hatsukami 1, Kelli Skoog 1, Marguerite Huber 1, and John Hughes 2 1 Universityof Minnesota, Department of Psychiatry,Box 392 Mayo, Minneapolis, MN 55455, USA 2 Universityof Vermont, Department of Psychiatry,College of Medicine, Burlington,VT 65405, USA Received June 19, 1990 / Final version November 12, 1990
Abstract. This study examined and compared withdrawal signs and symptoms from cessation of 0, 2 and 4 mg nicotine gum. In addition, a comparison was made between nicotine gum versus cigarette withdrawal symptoms. Smokers first underwent cigarette deprivation for 4 days and then were randomly assigned to 0 (N= 16), 2 (N= 25), and 4 (N= 21) mg gum. They were asked to chew the gum for 1 month and then to undergo a 4-day nicotine gum deprivation period. The results showed a number of significant changes occurring after deprivation from 4 mg gum, one change from 2 mg gum, and no changes from 0 mg gum. There were no significant differences in severity of withdrawal among the various doses of nicotine gum. There were more severe symptoms of withdrawal from cigarette as opposed to 4 mg nicotine gum deprivation. Key words" Nicotine gum
Cigarette - Withdrawal
Significant signs and symptoms of withdrawal have been found after cigarette and smokeless tobacco deprivation (USPHS 1988; Hughes et al. 1989a). The question arises as to whether these signs and symptoms are due exclusively to the effects of nicotine or from other constituents of smoke and tobacco exposure. There are three ways to answer this question. One way is to examine whether a nicotine antagonist precipitates withdrawal signs and symptoms. Mecamylamine, a CNS nicotine blocker, has produced equivocal results in its ability to precipitate withdrawal signs and symptoms (Stolerman et al. 1973; Tennant et al. 1984; Nemeth-Coslett et al. 1986). In fact, a recent review reported that mecamylamine may not be a potent blocker of the cholinergic nicotine receptor (Hughes et al. 1989a) Thus, if withdrawal signs and symptoms are associated with cholinergic nicotine receptors, mecamylamine would not be expected to precipitate withdrawal. Offprint requests to. D.K. Hatsukami
Another method to determine whether withdrawal signs and symptoms are due to nicotine is to see whether nicotine can alleviate these signs and symptoms. Several studies have carefully and specifically examined whether nicotine gum can alleviate withdrawal symptoms which are experienced after giving up smoking (Jarvis et al. 1982; Hughes et al. 1984; Schneider et al. 1984; West et al. 1984; Gross and Stitzer 1989). In general, the studies showed that nicotine gum does alleviate some of the symptoms of withdrawal, most notably anxiety, irritability, and decreased concentration, but does not alleviate others, particularly craving. The final way is to examine the changes which occur after deprivation fi'om nicotine alone. Two studies have examined the withdrawal effects after deprivation from 2 mg nicotine gum (West and Russell 1985; Hughes et al. 1986). These studies found signs and symptoms of nicotine withdrawal to be similar to that of tobacco withdrawal. Both studies, however, included only subjects who had used nicotine gum for at least a year or had used for median of 5 months, thus, biasing the sample to those who are behaviorally dependent on the gum. No study has yet examined withdrawal symptoms from nicotine gum in smokers who have never used the gum and who are randomly assigned to different doses of nicotine gum. Furthermore, no study has yet examined withdrawal from 4 mg gum which produces higher levels of nicotine than 2 mg gum. In the present study, we examined and compared withdrawal signs and symptoms from cessation of 0, 2, and 4 mg nicotine gum. We also compared withdrawal symptoms from nicotine gum cessation versus cigarette cessation. Smokers who were motivated to quit smoking first underwent cigarette deprivation for 4 days and then were randomly assigned to one of three doses of nicotine gum 0, 2 or 4 mg. They were asked to chew the gum for 1 month and then to stop chewing gum for a period of 4 days. This study thus provides further empirical information regarding the extent to which signs and symptoms of tobacco withdrawal can be attributed to the nicotine itself and whether withdrawal from nicotine
497 g u m is dose related. A d d i t i o n a l l y , this s t u d y also provides a direct c o m p a r i s o n o f the w i t h d r a w a l f r o m signs a n d s y m p t o m s f r o m cigarettes a n d n i c o t i n e g u m e m p l o y i n g a w i t h i n - s u b j e c t design. F i n a l l y , the results f r o m this study will have clinical utility in d e t e r m i n i n g to w h a t extent s m o k e r s m a y b e c o m e physically d e p e n d e n t o n the gum.
Materials and methods
Subjects. Subjects were adult smokers recruited by newspaper advertisements. Subjects were recruited if they smoked at least a pack of cigarettes/day, were motivated to quit smoking (rated > 7 on an analogue scale ranging from 0 to 10 inquiring on the subjects motivation to quit), and had never used nicotine gum. All subjects also fulfilled DSM-III criteria for tobacco dependence (i.e., use tobacco for 1 month plus prior failure to stop smoking, tobacco withdrawal symptoms, or use despite smoking aggravated illness) and a past history of tobacco withdrawal syndrome. Subjects were excluded from the study if they had medical contraindications to nicotine gum, were presently or planned to be pregnant, had a history of alcohol or drug abuse, past and current psychiatric diagnoses, or were taking psychoactive medications. Informed consent was obtained from all subjects prior to acceptance into the study. Procedure. Subjects were involved in the study for a total of 6 weeks. In week 1, subjects were tested for signs and symptoms of cigarette withdrawal. In weeks 2-5, subjects were asked to chew one of three doses of nicotine gum. In week 6, subjects were tested for signs and symptoms of nicotine gum withdrawal. During the first week, subjects smoked their usual number and brand of cigarettes for 2 days and then underwent a 4-day cigarette deprivation period. Subjects attended five individual late afternoon sessions of 30-45 min duration. At each session, subjects were administered a battery of withdrawal measures (see below) during the 2 days of baseline cigarette smoking (Sunday and Monday) and 3 of the 4 days of cigarette deprivation (Tuesday, Wednesday and Friday). Subjects who were unable to stop smoking (e.g. smoked any cigarettes) during the cigarette deprivation phase of the study were dropped. After the session on Friday of the first week of the study, subjects were randomly assigned in a double-blind fashion to 0, 2 or 4 mg gum. Subject were asked to chew at least six pieces/day of the assigned gum on an ad-lib basis for the next 4 weeks (weeks 2-5). The first two groups (N= 15) were required to chew at least three pieces of nicotine gum/day. However because a significant number chewed only the required pieces of gum, the minimum was raised to six pieces of gum for the subsequent groups of subjects. The number of subjects were equally distributed across doses (0 mg = 4; 2 mg = 6; 4 mg= 5). Subjects were seen briefly each week during this time to facilitate abstinence from smoking and obtain more gum. During each session, the subject was asked about his/her smoking status, gum use, and side effects from the gum. In addition, smoking cessation techniques were discussed as described in "Quit to Win" a self-help treatment manual (Pechacek et al. 1982) given to the subjects during the first week.
During the last week of the study, only subjects who had been able to maintain abstinence from tobacco for the 4 full weeks were allowed to participate. During this week (week 5), subjects were administered the battery of withdrawal measures during 2 days of ad-lib gum chewing (Sunday and Monday). Subjects were asked to quit chewing the nicotine gum after the Monday session and then were tested on the withdrawal battery on 3 of the 4 days during nicotine gum deprivation (Tuesday, Wednesday and Friday). Subjects were required to maintain the same level of alcohol and caffeine use. They were also asked to refrain from caffeine or food intake for 1 h prior to the testing sessions, and not to use any drugs or alcohol at least 8 h before the testing sessions. These measures were employed to minimize the effects of other drugs on the measures of withdrawal. The amount of daily alcohol and caffeine use and time since last use of alcohol and caffeine were measured by self-report Subjects submitted breath samples for carbon monoxide analysis and saliva thiocyanate and cotinine samples to verify smoking abstinence, and (where applicable) salivary samples for cotinine to verify gum use. Subjects were paid $200 if they complied with the experimental procedures. The battery of measures administered to the subjects included physiological, subjective, and behavioral measures. These measures were selected from previous studies we have conducted to determine sensitive and reliable indicators of tobacco withdrawal (Hatsukami et al. 1984; Hughes and Hatsukami 1986). Physiological measures included heart rate and body weight. Subjective measures included a 100 mm visual analog "craving for tobacco" line and a self-rated withdrawal symptoms checklist, found to be a reliable, valid and sensitive measure of tobacco withdrawal symptoms (Hughes and Hatsukami 1986; Hatsukami et al. 1987). This checklist involved rating the following symptoms on a 0-5 scale in which 0 = none and 5 = severe: irritable/angry, anxious/tense, difficulty concentrating, restless, impatient, excessive hunger, somatic symptoms (e.g., sweating, dizziness, and stomach problems), insomnia, increased eating, and drowsiness. A total withdrawal score was obtained by summing the responses (with the exception of the last two items). In addition, the Stanford Sleep Scale, which measures number of awakenings and quality of sleep among other sleep variables (Carskadon et al. 1976), and a 24 h dietary recall form were administered. Behavioral measures included a reaction time and response inhibition task previously shown sensitive to tobacco withdrawal (Hughes et al. 1989b). In this task, subjects were to press a button
Table 1. Demographics and smoking history for the 0, 2, and 4 mg nicotine gum groups 0 mg N=ll
2 mg N=18
4 mg N=19
Sex
Female Male Age Cig/day Nic yield Yrs smoked
5 6 31.9 4-8.9 30.1 4-9.7 0.804-0.20 15.6 4-9.2
9 9 34.6 4-9.4 27.0 4-7.4 0.744-0.22 15.7 4-8.6
10 9 32.5 4-6.8 27.7 4-7.8 0.784-0.39 15.3 4-9.0
Table 2. Saliva cotinine levels (X 4- SE) during cigarette baseline, gum baseline and gum deprivation among subjects assigned to 0, 2 and 4 mg nicotine gum"
Cotinine levels
0 mg
2 mg
4 mg
Cigarette baseline Gum baseline* Gum deprivation
276.71 £ 66.37 (N= 7) 2.71 £ 2.55 (N= 7) 0.434- 0.43 (N=6)
256.87 + 32.16 (N = 15) 84.44 + 34.23 (N = 8) 7.834- 3.26 (N=6)
294.20 4- 38.43 (N= 15) 265.80 4- 58.96 (N = 10) 10.624- 5.52 (N=7)
a Samples were randomly chosen to be sent to the laboratory for analysis. * P_
