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Evaluation of cranial electrostimulation therapy on short-term smoking cessation
Evaluation of Cranial Electrostimulation Therapy on Short-Term Smoking Cessation Wallace B. Pickworth, Reginald V. Fant, Marsha F. Butschky, Allison L. Goffman, and Jack E. Henningfield
The effects of cranial electrical stimulation (CES) on short-term smoking cessation were evaluated in a double-blind study of cigarette smokers who wished to stop smoking. Subjects were randomly assigned to a CES- (n = 51) or a sham-treated group (n = 50). On 5 consecutive days subjects received CES treatments (30-t~A, 2-msec, IO-Hz pulsed signal) or no electrical current (sham). There were no significant differences between groups on daily cigarettes smoked, exhaled carbon monoxide, urinary cotinine levels, treatment retention, smoking urges, or total tobacco withdrawal scores, although subjects in the CES group had less cigarette craving and anxiety during the first 2 experimental days. The ineffectiveness of CES to reduce withdrawal symptoms and facilitate smoking cessation are similar to results of other clinical studies of CES in drug dependence, although positive effects of CES in animal studies have been reported. © 1997 Society of Biological Psychiatry Key Words: Cranial electrostimulation, tobacco withdrawal, smoking cessation BIOL PSYCHIATRY 1997;42:116--121
Introduction Nicotine replacement therapy reduces tobacco withdrawal symptoms and improves abstinence rates (Henningfield 1995; Gross and Stitzer 1989); however, its overall success rate is low. Some patients cannot use these medications (Henningfield 1995), and others object to the continued use of nicotine as a replacement medication. These considerations led us to evaluate a nondrug therapy in a smoking cessation study. Cranial electrostimulation (CES), the application of
From the National Institute on Drug Abuse, Addiction Research Center, Clinical Pharmocology Branch, Baltimore, Maryland. Address reprint requests to Wallace B. Pickworth, PhD, Clinical Pharmacology Branch, NIDA, Addiction Research Center, P.O. Box 5180, Baltimore, MD 21224. Received December 18, 1995; revised April 29, 1996.
© 1997 Society of Biological Psychiatry
electrical currents from surface electrodes, has been used for the treatment of insomnia, anxiety, and withdrawal symptoms from the discontinuation of opiates and cocaine (review: Alling et al 1990; Gariti et al 1992). Lowamperage, low-frequency alternating current reduced symptoms of opiate withdrawal and craving (Patterson et al 1984). Gariti et al (1992) used CES to treat opiate and cocaine withdrawal and Jasinski et al (1992) reported that CES reduced tobacco withdrawal. The CES used in the present study and the Jasinski et al (1992) study was below the threshold of perception. This enabled us to design a double-blind, sham-controlled evaluation of CES during tobacco withdrawal. The purposes of the study were to determine if subjects in the CES-treated group experienced less withdrawal, smoked fewer cigarettes, and had a higher treatment retention than those in the sham-treated group. 0006-3223/97/$17.00 PII S0006-3223(96)00294-6
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Table 1. Subject Characteristics in CES and SHAM Treated Groups
Number Men Women Age (yr) Cigs/day Yrs smoking Age smoking onset (yr) Carbon monoxide (ppm) Fagerstrrm score*
CES
SHAM
51 27 24 44.2 31.9 28.7 17.2 24.3 7.9
50 21 29 46.3 30.6 27.1 16.9 23.5 7.2
Values are the means of the CES (cranial electrostimulation) and SHAM (no current) groups. Differences were not significantby Chi Square or t-tests except for * Fagerstrrm (1978) scores [t(99) = 2.4, p < .02].
Methods Subjects Of 194 subjects recruited from the community, 28 were found ineligible at an orientation session, and 45 did not report for the first session. Of the 121 subjects that began the study, 101 completed (Table 1). Inclusion criteria included: over 21 years old, smoke more than 20 cigarettes per day for at least 1 year, use no tobacco products other than cigarettes, able and willing to refrain from psychoactive medications, and willing to attend five study sessions on consecutive days. Exclusion criteria included: pregnancy, a positive drug history, the current care of a physician for any condition that could have interfered with the study, any implanted medical devices, and a personal or family history of seizures or migraine headaches. Eligibility was determined by medical history, vital sign measures, and a urine specimen, which was used to screen for pregnancy and illicit drugs (opiates, cocaine, phencyclidine, marijuana, benzodiazepines, and barbiturates). Subjects signed informed consent documents that had been approved by the hospital institutional review board. The study met the Department of Health and Human Services guidelines for the treatment of research volunteers.
Procedures ORIENTATION SESSION. At an orientation session, the purpose and procedures of the study were explained and the informed consent document was signed. A brief medical examination was performed and a personal and family medical history were obtained. A urine sample was collected and analyzed for cotinine (Hariharan et al 1988), drugs, and pregnancy. Exhaled carbon monoxide (CO) was measured (Ecolyzer, National Draeger Instruments, Pittsburgh, PA). Questionnaires measuring affective inten-
sity, mood, nicotine tolerance, nicotine withdrawal, and tobacco craving were completed. Subjects were instructed to stop smoking the night before their first treatment session and to continue tobacco abstinence during the 5-day study. RANDOMIZATION AND BLINDING. Neuromedical Technologies Inc. (Herndon, VA) prepared sealed envelopes containing a cartridge and an insert that was randomly assigned to each subject. After the study, the treatment each subject received was identified. Since the electrical stimulation delivered by CES is below the level of detection, neither the subjects nor the investigators knew the treatment. EXPERIMENTAL SESSIONS. Subjects reported to the treatment room once daily for 5 consecutive days. Vital signs and CO were recorded and subjects completed questionnaires that assessed tobacco withdrawal, mood, and smoking urges (see Procedures). Subjects reported the number of cigarettes smoked in the past 24 hours. An electrode (pediatric red dot, 3M) was placed on each mastoid process, the positive electrode on the dominant side. Participants sat for the 60 min that the CES or sham was delivered. After the treatment, vital signs and the mood questionnaire were repeated. On day 5, a urine sample for cotinine analysis was obtained and copies of the withdrawal scale, smoking urge questionnaire, and the cigarettes smoked questionnaire were distributed. These questionnaires, describing the effects of the last experimental treatment, were mailed to the investigators. Subjects were contacted 1 month later to determine their smoking status. STIMULATION PARAMETERS. Neuromedical Technologies Inc. supplied the CES device and determined the stimulation parameters based on proprietary data from clinical and animal studies. The CES was a low-frequency (10 Hz), 2-msec pulsed signal delivered to skin electrodes on the mastoid process. The device automatically adjusted stimulation strength when electrode impedance changed so that CES-treated subjects received 30 txA per stimulus pulse throughout the 60-rain session. The insert in the sham-treated subjects contained a high-impedance shunt, which interrupted the current before reaching the electrodes.
Measures TOBACCO WITHDRAWAL SYMPTOMS. Tobacco withdrawal symptoms were measured with a nine-item withdrawal scale (Hughes and Hatsukami 1986). The subjects were asked to rate those symptoms which were experi-
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enced in the last 24 hours on a scale of 0 to 5. This questionnaire was administered on seven occasions: on orientation day, before the treatments, and on day 6. CRAVING. A short form (10 items) of the Questionnaire of Smoking Urges (QSU; Tiffany and Drobes 1991) was used to evaluate cigarette craving. Factor 1 scale items reflect intention and desire to smoke and anticipation of pleasure from smoking. Factor 2 items reflect urgent and overwhelming desire to smoke and anticipation of relief from tobacco withdrawal. This questionnaire was administered on orientation day, before the treatments, and on day 6. MOOD. Mood was assessed using a nine-item mood questionnaire (Diener and Larsen 1984). Subjects indicated how much he/she was experiencing positive and negative mood items. The questionnaire was administered before and after treatments. SMOKING
BEHAVIOR.
The
number
of
cigarettes
smoked was obtained by self-report and was verified with exhaled CO. These measures were obtained prior to treatment on each of the five experimental days. Urinary levels of cotinine, the major metabolite of nicotine, were measured from samples obtained at orientation and after the treatment on day 5. VITAL SIGNS. Respiration rate, seated blood pressure, heart rate, and oral temperature were measured prior to and following treatments.
Statistical Analysis Analysis of variance (ANOVA) techniques were used to assess treatment effects across session days (Winer et al 1991). Withdrawal, craving, and smoking behavior were assessed using two-way ANOVAs with group (sham, CES) as a between-subjects factor and measurement day as a within-subjects factor. Mood and vital signs were assessed using three-way ANOVAs. Tukey's honestly significant difference test was used in post hoc analyses. Results
Smoking Behavior Smoking and exhaled CO dramatically decreased during the study (Figure 1). There was a significant main effect of day [smoking: F(4,396) = 94.8, p < .001; CO: F(4,396) = 29.9, p < .001], but there was no difference between the groups, nor was there a group by day interaction. In cotinine samples (n = 81; 38 sham, 43 CES) collected at orientation, levels averaged 1.8 mg/mL in the
25-
Cigarettes per Day
t..
20. H z
15.
10. 5-
0-
A Exhaled CO
20-
15-
10-
.
B Day
Figure 1. Comparison of CES-treated (n = 51) • and shamtreated (n = 50) [] subjects on measures (mean --- SEM) of self-reported daily smoking (A) and exhaled carbon monoxide, CO (B). sham group and 1.6 mg/mL in the CES group. On day 5, levels averaged 1.2 mg/mL in the sham group and 1.1 mg/mL in the CES group. There was no significant difference between the groups; however, there was a significant difference between orientation and day 5 levels [F(1,79) = 34.1, p < .001].
Tobacco Withdrawal Symptoms There was a significant change in total tobacco withdrawal scores across days [F(6,564) = 7.7, p < .001]. Changes across days were not related to treatment (Figure 2A). Scores on individual items of the tobacco withdrawal scale were measured separately. Scores on items of cigarette craving and anxiety (Figure 2B and C) were marginally affected by CES treatment [cigarette craving group by day interaction: F(6,564) = 1.9, p < . 10; anxiety: F(6,564) = 1.9, p < . 10]. Craving scores were reduced more on days 2 and 3 in the CES condition than in the sham condition. Anxiety scores on day 2 decreased in the CES condition, but increased in the sham condition. Twenty-nine (13 CES; 16 sham) of the subjects smoked less than four cigarettes on each study day. Comparable results were found on withdrawal measures in this subset of subjects as with the entire sample.
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between the groups on either of the two factor scores, nor was there a group by day interaction.
Total
45:
Mood There were no significant differences on mood scores between the groups, nor were there significant grouprelated interactions.
50
A i
Vital Signs i
s
i
i
i
!
!
There were no significant differences between the groups on measures of heart rate, systolic and diastolic blood pressure, respiration rate, or skin temperature, nor were there significant group-related interactions.
Craving
Retention There was no difference in rates of retention among subjects enrolled in the groups. In the sham-treated group, 50 of 60 subjects (83%) completed the study; in the CES-treated group 51 of the 61 subjects (84%) completed the study. i
!
i
!
i
i
Anxiety
5-
I
i
Follow-Up Of the 101 subjects who completed the study, 2 (both CES-treated) were lost to follow-up. There was no difference between the groups with regard to abstinence at 1-month follow-up. In the sham-treated group, 12 of the 50 subjects (24%) were abstinent on day 5, and 8 (16%) remained abstinent at follow-up. In the CES-treated group, 14 of the 51 subjects (27%) were abstinent on day 5, and 7 (14%) remained abstinent at follow-up.
432 1
C Day Figure 2. Comparison (mean ___SEM) of CES-treated (n = 51) • and sham-treated (n = 50) [] subjects on total withdrawal score (A), the cigarette craving item (B), and the anxiety item (C) of a tobacco withdrawal scale (Hughes and Hatsukami 1986). Scores for days 1-5 were obtained prior to the treatments; scores on day 0 were obtained at an orientation session; scores on day 6 were obtained from a mail-in questionnaire. *Indicates a significant difference between groups.
Questionnaire on Smoking Urges (QSU) Both factors of the QSU demonstrated significant day effects [Factor 1: F(6,564) = 53.9, p < .001; Factor 2: F(6,564) = 27.4, p < .001)]. Factor 1 scores were highest on day 0 and decreased steadily during experimental days. Factor 2 scores increased slightly from day 0 to day 1, then decreased over subsequent days. There was no difference
Discussion The results of the present evaluation of CES on smoking cessation indicated that the treatment caused a small decrease in some tobacco withdrawal symptoms, but did not significantly affect overall withdrawal or patterns of cigarette use. These results are similar to those of Jasinski et al (1992), who evaluated CES using a similar protocol. CES reduced tobacco withdrawal on days 2 and 5, but no reduction in cigarette craving or smoking behavior was evident (Jasinski et al 1992). Although there was a dramatic decrease in smoking, very few of the subjects were completely abstinent during the study. Smoking even a few cigarettes substantially reduces tobacco withdrawal (Hughes et al 1990), suggesting that the nicotine withdrawal syndrome was not fully developed and the potential benefits of CES could not be expressed. It is also possible that the continued administration of nicotine reduces the benefits of CES. Patterson et al (1984) noted
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that concomitant drug use diminishes the effectiveness of CES. The modest effect of CES on tobacco withdrawal symptoms is similar to its limited effectiveness in other drug withdrawal conditions. Gariti et al (1992) reported no significant CES-effects on opiate and cocaine withdrawal or drug craving. Gossop et al (1984) reported that CES was inferior to methadone treatment in the management of opiate withdrawal. In some treatment studies, positive results were reported. CES reduced acute and chronic withdrawal symptomatology and diminished craving from several classes of abused drugs including nicotine (Patterson et al t984). CES reduced anxiety and insomnia in depressed patients undergoing washout from their treatment drugs (Philip et al 1991). There has been no agreement on the optimal stimulation parameters, electrode position, or length of treatment to evaluate the effectiveness of CES in drug withdrawal. Similar stimulation parameters were used in the present study and the Jasinski et al (1992) study, but the position of the electrodes (earlobes versus mastoid) and the type of electrode (stainless steel, screw-down versus media saturated, self-adhesive) differed. Gariti et al (1992) used stronger current and frequencies (10 and 2000 Hz) than those of the present study for up to 10 days. Current was delivered between electrodes applied to an eyelid and the mastoids for 30 rain, twice daily in the Philip et al (1991)
W.B. Pickworth et al
study. Stimulation parameters may be optimized for the drug dependency being treated (Patterson et al 1984); however, a survey of the literature suggests little correlation between stimulus parameters and efficacy. Although the usefulness of CES in the clinical treatment of drug withdrawal remains unproven, the results of animal studies are generally more positive. Limoge-type CES potentiated opiate analgesia (Stinus et al 1990; Auriacombe et al 1990) and diminished opiate withdrawal (Auriacombe et al 1990) in rats. Malin et al (1988) reported that CES reduced the intensity of opiate withdrawal in rats and that this effect was blocked by naloxone. Preliminary data indicated that CES reduced nicotine withdrawal in rats (Manltsby et al 1991). Our results suggest only limited efficacy of CES in reducing tobacco withdrawal symptoms and no efficacy in reducing tobacco intake. It is possible that stimulation parameters specific for a drug-dependent state might prove efficacious; however, presently available evidence provides little basis for clinical application of CES for smoking cessation. Partial financial support and the CES equipment for the study were provided by Neuromedical Technologies Inc., Herndon, VA. The authors gratefully acknowledge the critical comments of Donald R. Jasinski, MD for his suggestions about study design and analysis. The nursing support of Joyce Lutz, RN and Kathy Demuth, RN and the technical support of Marc Holden and Janeen Nichels are appreciated.
References Alling FA, Johnson BD, Elmoghazy E (1990): Cranial electrostimulation (CES) use in the detoxification of opiate-dependent patients. J Subst Abuse Treat 7:173-180. Auriacombe M, Tignol J, Le Moal M, Stinus L (1990): Transcutaneous electrical stimulation with Limoge current potentiates morphine analgesia and attenuates opiate abstinence syndrome. Biol Psychiatry 28:650-656. Diener E, Larsen RJ (1984): Temporal stability and crosssituational consistency of affect, behavioral, and cognitive responses. J Pers Soc Psychol 47:580-592. Fagerstr6m KO (1978): Measuring degrees of nicotine dependency to tobacco smoking with reference to individualization of treatment. Addict Behav 3:235-241. Gariti P, Auriacombe M, Incmikoski R, et al (1992): A randomized double-blind study of neuroelectric therapy in opiate and cocaine detoxification. J Subst Abuse 4:299-308. Gossop M, Bradley B, Strang J, Connell P (1984): The clinical effectiveness of electrostimulation vs oral methadone in managing opiate withdrawal. Br J Psychiatry 144:203-208. Gross J, Stitzer ML (1989): Nicotine replacement: Ten-week effects of tobacco withdrawal symptoms. Psychopharmacology 98:334-341. Hariharan M, VanNoord T, Greden JF (1988): A high-perfor-
mance liquid-chromatographic method for routine simultaneous determination of nicotine and cotinine in plasma. Clin Chem 34:724-729. Henningfield JE (1995): Nicotine medications for smoking cessation. N Engl J Med 333:1196-1203. Hughes JR, Hatsukami DK (1986): Signs and symptoms of tobacco withdrawal. Arch Gen Psychiatry 43:289-294. Hughes JR, Higgins ST, Hatsukami DK (1990): Effects of abstinence from tobacco. In Kozlowski LT et al (eds), Research Advances in Alcohol and Drug Problems. vol 10. New York: Plenum Press, pp 317-398. Jasinski DR, Sullivan JT, Testa M, Preston K (1992): Reduction of tobacco withdrawal symptoms by transcranial electrostimulation therapy (TCET). In Harris LS (ed), NIDA Research Monograph #119: Problems of Drug Dependence.
CPDD Annual Scientific Meeting Abstracts 1991. USDHHS, p 329. Malin DH, Murray JB, Crucian GP, Schweitzer FC, Cook RE, Skolnick MH (1988): Auricular microstimulation: Naloxonereversible attenuation of opiate abstinence syndrome. Biol Psychiatry 24:886-890. Maultsby PN, Lake JR, Cortes CW, et al (1991): Animal model
CES in Smoking Cessation
of nicotine dependence and abstinence syndrome. Soc Neurosci Abs 17:1251. Patterson MA, Firth J, Gardiner R (1984): Treatment of drug, alcohol and nicotine addiction by neuroelectric therapy: Analysis of results over 7 years. J Bioelectricity 3:193-221. Philip P, Demotes-Malnard J, Bourgeois M, Vincent JD (1991): Efficiency of transcranial electrostimulation on anxiety and insomnia symptoms during a washout period in depressed patients a double-blind study. Biol Psychiatry 29:451-456.
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Stinus L, Auriacombe M, Tognol J, Limoge A, Le Moal M (1990): Transcranial electrical stimulation with high frequency intermittent current (Limoge's) potentiates opiateinduced analgesia: Blind studies. Pain 42:351-363. Tiffany ST, Drobes DJ (1991): The development and initial validation of a questionnaire on smoking urges. Br J Addict 86:1467-1476. Winer B J, Brown DR, Michels KM (1991): Statistical Principles in Experimental Design, 3rd ed. New York: McGraw Hill.
The effects of cranial electrical stimulation (CES) on short-term smoking cessation were evaluated in a double-blind study of cigarette smokers who wished to stop smoking. Subjects were randomly assigned to a CES- (n = 51) or a sham-treated group (n = 50). On 5 consecutive days subjects received CES treatments (30-t~A, 2-msec, IO-Hz pulsed signal) or no electrical current (sham). There were no significant differences between groups on daily cigarettes smoked, exhaled carbon monoxide, urinary cotinine levels, treatment retention, smoking urges, or total tobacco withdrawal scores, although subjects in the CES group had less cigarette craving and anxiety during the first 2 experimental days. The ineffectiveness of CES to reduce withdrawal symptoms and facilitate smoking cessation are similar to results of other clinical studies of CES in drug dependence, although positive effects of CES in animal studies have been reported. © 1997 Society of Biological Psychiatry Key Words: Cranial electrostimulation, tobacco withdrawal, smoking cessation BIOL PSYCHIATRY 1997;42:116--121
Introduction Nicotine replacement therapy reduces tobacco withdrawal symptoms and improves abstinence rates (Henningfield 1995; Gross and Stitzer 1989); however, its overall success rate is low. Some patients cannot use these medications (Henningfield 1995), and others object to the continued use of nicotine as a replacement medication. These considerations led us to evaluate a nondrug therapy in a smoking cessation study. Cranial electrostimulation (CES), the application of
From the National Institute on Drug Abuse, Addiction Research Center, Clinical Pharmocology Branch, Baltimore, Maryland. Address reprint requests to Wallace B. Pickworth, PhD, Clinical Pharmacology Branch, NIDA, Addiction Research Center, P.O. Box 5180, Baltimore, MD 21224. Received December 18, 1995; revised April 29, 1996.
© 1997 Society of Biological Psychiatry
electrical currents from surface electrodes, has been used for the treatment of insomnia, anxiety, and withdrawal symptoms from the discontinuation of opiates and cocaine (review: Alling et al 1990; Gariti et al 1992). Lowamperage, low-frequency alternating current reduced symptoms of opiate withdrawal and craving (Patterson et al 1984). Gariti et al (1992) used CES to treat opiate and cocaine withdrawal and Jasinski et al (1992) reported that CES reduced tobacco withdrawal. The CES used in the present study and the Jasinski et al (1992) study was below the threshold of perception. This enabled us to design a double-blind, sham-controlled evaluation of CES during tobacco withdrawal. The purposes of the study were to determine if subjects in the CES-treated group experienced less withdrawal, smoked fewer cigarettes, and had a higher treatment retention than those in the sham-treated group. 0006-3223/97/$17.00 PII S0006-3223(96)00294-6
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Table 1. Subject Characteristics in CES and SHAM Treated Groups
Number Men Women Age (yr) Cigs/day Yrs smoking Age smoking onset (yr) Carbon monoxide (ppm) Fagerstrrm score*
CES
SHAM
51 27 24 44.2 31.9 28.7 17.2 24.3 7.9
50 21 29 46.3 30.6 27.1 16.9 23.5 7.2
Values are the means of the CES (cranial electrostimulation) and SHAM (no current) groups. Differences were not significantby Chi Square or t-tests except for * Fagerstrrm (1978) scores [t(99) = 2.4, p < .02].
Methods Subjects Of 194 subjects recruited from the community, 28 were found ineligible at an orientation session, and 45 did not report for the first session. Of the 121 subjects that began the study, 101 completed (Table 1). Inclusion criteria included: over 21 years old, smoke more than 20 cigarettes per day for at least 1 year, use no tobacco products other than cigarettes, able and willing to refrain from psychoactive medications, and willing to attend five study sessions on consecutive days. Exclusion criteria included: pregnancy, a positive drug history, the current care of a physician for any condition that could have interfered with the study, any implanted medical devices, and a personal or family history of seizures or migraine headaches. Eligibility was determined by medical history, vital sign measures, and a urine specimen, which was used to screen for pregnancy and illicit drugs (opiates, cocaine, phencyclidine, marijuana, benzodiazepines, and barbiturates). Subjects signed informed consent documents that had been approved by the hospital institutional review board. The study met the Department of Health and Human Services guidelines for the treatment of research volunteers.
Procedures ORIENTATION SESSION. At an orientation session, the purpose and procedures of the study were explained and the informed consent document was signed. A brief medical examination was performed and a personal and family medical history were obtained. A urine sample was collected and analyzed for cotinine (Hariharan et al 1988), drugs, and pregnancy. Exhaled carbon monoxide (CO) was measured (Ecolyzer, National Draeger Instruments, Pittsburgh, PA). Questionnaires measuring affective inten-
sity, mood, nicotine tolerance, nicotine withdrawal, and tobacco craving were completed. Subjects were instructed to stop smoking the night before their first treatment session and to continue tobacco abstinence during the 5-day study. RANDOMIZATION AND BLINDING. Neuromedical Technologies Inc. (Herndon, VA) prepared sealed envelopes containing a cartridge and an insert that was randomly assigned to each subject. After the study, the treatment each subject received was identified. Since the electrical stimulation delivered by CES is below the level of detection, neither the subjects nor the investigators knew the treatment. EXPERIMENTAL SESSIONS. Subjects reported to the treatment room once daily for 5 consecutive days. Vital signs and CO were recorded and subjects completed questionnaires that assessed tobacco withdrawal, mood, and smoking urges (see Procedures). Subjects reported the number of cigarettes smoked in the past 24 hours. An electrode (pediatric red dot, 3M) was placed on each mastoid process, the positive electrode on the dominant side. Participants sat for the 60 min that the CES or sham was delivered. After the treatment, vital signs and the mood questionnaire were repeated. On day 5, a urine sample for cotinine analysis was obtained and copies of the withdrawal scale, smoking urge questionnaire, and the cigarettes smoked questionnaire were distributed. These questionnaires, describing the effects of the last experimental treatment, were mailed to the investigators. Subjects were contacted 1 month later to determine their smoking status. STIMULATION PARAMETERS. Neuromedical Technologies Inc. supplied the CES device and determined the stimulation parameters based on proprietary data from clinical and animal studies. The CES was a low-frequency (10 Hz), 2-msec pulsed signal delivered to skin electrodes on the mastoid process. The device automatically adjusted stimulation strength when electrode impedance changed so that CES-treated subjects received 30 txA per stimulus pulse throughout the 60-rain session. The insert in the sham-treated subjects contained a high-impedance shunt, which interrupted the current before reaching the electrodes.
Measures TOBACCO WITHDRAWAL SYMPTOMS. Tobacco withdrawal symptoms were measured with a nine-item withdrawal scale (Hughes and Hatsukami 1986). The subjects were asked to rate those symptoms which were experi-
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enced in the last 24 hours on a scale of 0 to 5. This questionnaire was administered on seven occasions: on orientation day, before the treatments, and on day 6. CRAVING. A short form (10 items) of the Questionnaire of Smoking Urges (QSU; Tiffany and Drobes 1991) was used to evaluate cigarette craving. Factor 1 scale items reflect intention and desire to smoke and anticipation of pleasure from smoking. Factor 2 items reflect urgent and overwhelming desire to smoke and anticipation of relief from tobacco withdrawal. This questionnaire was administered on orientation day, before the treatments, and on day 6. MOOD. Mood was assessed using a nine-item mood questionnaire (Diener and Larsen 1984). Subjects indicated how much he/she was experiencing positive and negative mood items. The questionnaire was administered before and after treatments. SMOKING
BEHAVIOR.
The
number
of
cigarettes
smoked was obtained by self-report and was verified with exhaled CO. These measures were obtained prior to treatment on each of the five experimental days. Urinary levels of cotinine, the major metabolite of nicotine, were measured from samples obtained at orientation and after the treatment on day 5. VITAL SIGNS. Respiration rate, seated blood pressure, heart rate, and oral temperature were measured prior to and following treatments.
Statistical Analysis Analysis of variance (ANOVA) techniques were used to assess treatment effects across session days (Winer et al 1991). Withdrawal, craving, and smoking behavior were assessed using two-way ANOVAs with group (sham, CES) as a between-subjects factor and measurement day as a within-subjects factor. Mood and vital signs were assessed using three-way ANOVAs. Tukey's honestly significant difference test was used in post hoc analyses. Results
Smoking Behavior Smoking and exhaled CO dramatically decreased during the study (Figure 1). There was a significant main effect of day [smoking: F(4,396) = 94.8, p < .001; CO: F(4,396) = 29.9, p < .001], but there was no difference between the groups, nor was there a group by day interaction. In cotinine samples (n = 81; 38 sham, 43 CES) collected at orientation, levels averaged 1.8 mg/mL in the
25-
Cigarettes per Day
t..
20. H z
15.
10. 5-
0-
A Exhaled CO
20-
15-
10-
.
B Day
Figure 1. Comparison of CES-treated (n = 51) • and shamtreated (n = 50) [] subjects on measures (mean --- SEM) of self-reported daily smoking (A) and exhaled carbon monoxide, CO (B). sham group and 1.6 mg/mL in the CES group. On day 5, levels averaged 1.2 mg/mL in the sham group and 1.1 mg/mL in the CES group. There was no significant difference between the groups; however, there was a significant difference between orientation and day 5 levels [F(1,79) = 34.1, p < .001].
Tobacco Withdrawal Symptoms There was a significant change in total tobacco withdrawal scores across days [F(6,564) = 7.7, p < .001]. Changes across days were not related to treatment (Figure 2A). Scores on individual items of the tobacco withdrawal scale were measured separately. Scores on items of cigarette craving and anxiety (Figure 2B and C) were marginally affected by CES treatment [cigarette craving group by day interaction: F(6,564) = 1.9, p < . 10; anxiety: F(6,564) = 1.9, p < . 10]. Craving scores were reduced more on days 2 and 3 in the CES condition than in the sham condition. Anxiety scores on day 2 decreased in the CES condition, but increased in the sham condition. Twenty-nine (13 CES; 16 sham) of the subjects smoked less than four cigarettes on each study day. Comparable results were found on withdrawal measures in this subset of subjects as with the entire sample.
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between the groups on either of the two factor scores, nor was there a group by day interaction.
Total
45:
Mood There were no significant differences on mood scores between the groups, nor were there significant grouprelated interactions.
50
A i
Vital Signs i
s
i
i
i
!
!
There were no significant differences between the groups on measures of heart rate, systolic and diastolic blood pressure, respiration rate, or skin temperature, nor were there significant group-related interactions.
Craving
Retention There was no difference in rates of retention among subjects enrolled in the groups. In the sham-treated group, 50 of 60 subjects (83%) completed the study; in the CES-treated group 51 of the 61 subjects (84%) completed the study. i
!
i
!
i
i
Anxiety
5-
I
i
Follow-Up Of the 101 subjects who completed the study, 2 (both CES-treated) were lost to follow-up. There was no difference between the groups with regard to abstinence at 1-month follow-up. In the sham-treated group, 12 of the 50 subjects (24%) were abstinent on day 5, and 8 (16%) remained abstinent at follow-up. In the CES-treated group, 14 of the 51 subjects (27%) were abstinent on day 5, and 7 (14%) remained abstinent at follow-up.
432 1
C Day Figure 2. Comparison (mean ___SEM) of CES-treated (n = 51) • and sham-treated (n = 50) [] subjects on total withdrawal score (A), the cigarette craving item (B), and the anxiety item (C) of a tobacco withdrawal scale (Hughes and Hatsukami 1986). Scores for days 1-5 were obtained prior to the treatments; scores on day 0 were obtained at an orientation session; scores on day 6 were obtained from a mail-in questionnaire. *Indicates a significant difference between groups.
Questionnaire on Smoking Urges (QSU) Both factors of the QSU demonstrated significant day effects [Factor 1: F(6,564) = 53.9, p < .001; Factor 2: F(6,564) = 27.4, p < .001)]. Factor 1 scores were highest on day 0 and decreased steadily during experimental days. Factor 2 scores increased slightly from day 0 to day 1, then decreased over subsequent days. There was no difference
Discussion The results of the present evaluation of CES on smoking cessation indicated that the treatment caused a small decrease in some tobacco withdrawal symptoms, but did not significantly affect overall withdrawal or patterns of cigarette use. These results are similar to those of Jasinski et al (1992), who evaluated CES using a similar protocol. CES reduced tobacco withdrawal on days 2 and 5, but no reduction in cigarette craving or smoking behavior was evident (Jasinski et al 1992). Although there was a dramatic decrease in smoking, very few of the subjects were completely abstinent during the study. Smoking even a few cigarettes substantially reduces tobacco withdrawal (Hughes et al 1990), suggesting that the nicotine withdrawal syndrome was not fully developed and the potential benefits of CES could not be expressed. It is also possible that the continued administration of nicotine reduces the benefits of CES. Patterson et al (1984) noted
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that concomitant drug use diminishes the effectiveness of CES. The modest effect of CES on tobacco withdrawal symptoms is similar to its limited effectiveness in other drug withdrawal conditions. Gariti et al (1992) reported no significant CES-effects on opiate and cocaine withdrawal or drug craving. Gossop et al (1984) reported that CES was inferior to methadone treatment in the management of opiate withdrawal. In some treatment studies, positive results were reported. CES reduced acute and chronic withdrawal symptomatology and diminished craving from several classes of abused drugs including nicotine (Patterson et al t984). CES reduced anxiety and insomnia in depressed patients undergoing washout from their treatment drugs (Philip et al 1991). There has been no agreement on the optimal stimulation parameters, electrode position, or length of treatment to evaluate the effectiveness of CES in drug withdrawal. Similar stimulation parameters were used in the present study and the Jasinski et al (1992) study, but the position of the electrodes (earlobes versus mastoid) and the type of electrode (stainless steel, screw-down versus media saturated, self-adhesive) differed. Gariti et al (1992) used stronger current and frequencies (10 and 2000 Hz) than those of the present study for up to 10 days. Current was delivered between electrodes applied to an eyelid and the mastoids for 30 rain, twice daily in the Philip et al (1991)
W.B. Pickworth et al
study. Stimulation parameters may be optimized for the drug dependency being treated (Patterson et al 1984); however, a survey of the literature suggests little correlation between stimulus parameters and efficacy. Although the usefulness of CES in the clinical treatment of drug withdrawal remains unproven, the results of animal studies are generally more positive. Limoge-type CES potentiated opiate analgesia (Stinus et al 1990; Auriacombe et al 1990) and diminished opiate withdrawal (Auriacombe et al 1990) in rats. Malin et al (1988) reported that CES reduced the intensity of opiate withdrawal in rats and that this effect was blocked by naloxone. Preliminary data indicated that CES reduced nicotine withdrawal in rats (Manltsby et al 1991). Our results suggest only limited efficacy of CES in reducing tobacco withdrawal symptoms and no efficacy in reducing tobacco intake. It is possible that stimulation parameters specific for a drug-dependent state might prove efficacious; however, presently available evidence provides little basis for clinical application of CES for smoking cessation. Partial financial support and the CES equipment for the study were provided by Neuromedical Technologies Inc., Herndon, VA. The authors gratefully acknowledge the critical comments of Donald R. Jasinski, MD for his suggestions about study design and analysis. The nursing support of Joyce Lutz, RN and Kathy Demuth, RN and the technical support of Marc Holden and Janeen Nichels are appreciated.
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