- Email: [email protected]
The effects of high and low doses of methadone on cigarette smoking
fl.Sf,VIER SCIENCE IRELAhll
Drug and Alcohol
Dependence
34 (1994) 237-242
The effects of high and low doses of methadone on cigarette smoking Joy M. Schmitz *, John Grabowski,
Howard
Rhoades
Substance Abuse Reseurch Centre, Department of Psychiatry and Behuvioral Sciences. University of Texas Medical School. 1300 Mour.wnd .4 w Houston TX 77030, USA
(Accepted
27 July 1993)
Abstract The effect of methadone dose on the cigarette smoking of five methadone maintenance subjects was studied in a clinical setting. Following a two-week baseline period, daily doses of methadone were either increased (50-80 mg) or decreased (80-50 mg) every two weeks according to an A-B-A-B study design. Continuous self-monitoring was used to collect data on natural smoking behavior, and expired air carbon monoxide (CO) levels were measured at each clinic visit. The predicted methadone dose-related changes in smoking were found in three of the five subjects. Fine-grained analysis of self-monitoring records showed that the proportion of total daily smoking was highest within 4 h after taking methadone for three subjects. CO levels were not significantly associated with smoking rate. The results further support and extend previous reports that methadone may produce dose-related increases in smoking. No reactive effects of self-monitoring were observed, and compliance with this procedure was extremely high, supporting the usefulness of this method for assessing natural smoking behavior in this population. Key words:
Methadone
maintenance;
Tobacco
smoking;
Nicotine;
1. Intmduction
Tobacco dependence is common among users of other drugs, with smoking prevalence ranging from 85% to 100% in abusers of alcohol, opioids, and cocaine (Istvan and Matarazzo, 1984; Rounsaville et al., 1985; Burling and Ziff, 1988; DiFranza and Guerrera, 1990). The observed correlation between cigarette smoking and other drug use has been extended by laboratory studies demonstrating a more direct causal relationship between these variables, Acute administration of ethanol (Grifliths, Bigelow and Liebson, 1976; Mello et al., 1980a), heroin (Mello et al., 1980b), psychomotor stimulants (Schuster, Lucchesi and Emley, 1979; Henningfield and Griffiths, 1981), and sedatives (Henninglield, Chait and Grifliths, 1983) have produced increases in rates of cigarette smoking. Methadone itself has been shown to influence ciga-
* Corresponding author, University of Texas Mental Sciences Institute, 1300 Moursund, Houston, TX 77030, USA. 0 1994 Elsevier Science Ireland 0376-8716/94/$07.00 SSDI 0376-8716(93)0953-Y
Ltd. All rights
Self-monitoring
rette smoking in subjects maintained on methadone. Chait and Griffiths (1984), in the only published report to date, examined the interaction of acute methadone administration and smoking in five male methadone maintenance patients. Subjects participating in this controlled laboratory study were allowed to smoke ad libitum 90 min after receiving either a placebo, dextromethorphan, or one of three doses of methadone (0.5, 1.0, or 2.0 times their regular maintenance dose). It was found that methadone pretreatment produced substantial increases in cigarette smoking, level of carbon monoxide (CO), and subjective ratings of smoking satisfaction. This study represents the first attempt to use a nonlaboratory methodology to explore further the relationship between methadone administration and cigarette smoking. Five methadone maintenance patients recorded their daily smoking over an 8-week study period involving systematic methadone dose manipulations implemented under double blind conditions. The primary objectives were (a) to replicate the findings from laboratory studies in showing a dose-dependent relareserved
238
tionship between methadone and smoking, (b) to assess the extent to which natural smoking behavior could be recorded by self-monitoring procedures, and (c) to conduct a tine-grained analysis of the relationship between daily methadone ingestion and subsequent smoking for individual subjects. The study was reviewed and approved by the Committee for the Protection of Human Subjects of the University of Texas Health Science Center. 2. Methods 2.1. Subjects
Five patients enrolled in an outpatient methadone maintenance treatment research program at the University of Texas, Department of Psychiatry and Behavioral Sciences, Addictive Behaviors Clinic in Houston, Texas, participated in this study. To be eligible to participate, subjects had to (a) be regular cigarette smokers defined as at least 10 cigarettes per day; (b) have smoked for at least 12 months prior to the study; and (c) have a baseline expired-air carbon monoxide (CO) level of at least 15 parts per million (ppm). All had lengthy histories of opiate addiction. Subjects with significant medical or psychiatric disturbance were excluded. Characteristics of the study participants are presented in Table 1. Since this study focuses specifically on the relationship between methadone and nicotine, other concurrent drug use, with the exception of caffeine, was an exclusion criterion. Urinalysis results collected at our clinic during the 6-month study period preceding the present study were reviewed to determine regular use of other drugs or alcohol. Nine subjects were excluded from entry to the study by using this criterion. 2.2. Measurement
Daily smoking behavior was measured in two ways: by self-monitoring techniques and by expired air CO. Self-monitoring was implemented by instructing the subject to record each cigarette smoked according to the hour of the day. This information was recorded on small pre-printed cards cut to fit inside the cellophane wrapper of a cigarette package. In addition to recording cigarettes, subjects were instructed to indicate on the card the exact time of methadone ingestion each day. A Smoking History Questionnaire was used to assess smoking relevant variables (e.g., rate, duration) and included the Fagerstrom Tolerance Questionnaire (FTQ: Fagerstriim, 1978). Alveolar carbon monoxide (CO) levels were measured with the MiniCO Model 1000 portable ecolyzer (Catalyst Research Corporation, Owings Mills, MD). Subjects were not shown their CO values at the time of collection. Since cigarette smoking immediately before CO measurement is known to artificially inflate values (Hughes, Frederiksen and Frazier, 1978), subjects were asked to refrain from smoking at
J.M. Schmirz et al. /Drug
and Alcohol Depmd.
34 (1994) 237-242
least 30 min prior to collection. Before taking the CO test, time since the last cigarette was recorded. 2.3. Methadone dose manipulation
This study employed a within-subject A-B-A-B design to assess the influence of methadone dose on smoking behavior in the natural environment. Methadone dosage was either increased (SO-SO mg) or decreased (SO-SO mg) over successive 2-week intervals following a 2-week baseline period. For example, subjects on 50 mg during the 2-week baseline (A) were switched to the alternate dose (80 mg) for a 2-week period (B), and 2 weeks later, returned to the original dose (A). This increase-decrease cycle was repeated once, resulting in a total study duration of 8 weeks. Dose switches were made according to a 3-day, lo-mg dose increment (decrement) procedure. 2.4. Procedure
Subjects were recruited for this study during their final week of participation in a treatment study in which each patient was maintained on either 50 mg or 80 mg methadone (determined by random assignment) for the entire 6-month study period. This maintenance dose was set as the baseline condition for the present study. The 2-week baseline period allowed subjects to adapt to the self-monitoring and other study procedures. Study participants attended the clinic three times per week (Monday, Wednesday, and Friday) to ingest methadone delivered in a cherry syrup vehicle (Methadose@‘) under nursing supervision. Medicating times were 8:00 a.m. for all subjects. Individually packaged take-home doses of methadone were provided on remaining days. Dosages were letter-coded to provide some degree of blindness on the part of subjects, nurses, and research assistants regarding the experimental condition. Each methadone dose was associated with a specific letter. Subjects were not told of the coding system (i.e., that different letters signified different doses of methadone). At the initial clinic visit before the start of the study, patients signed the informed consent form and completed a smoking history questionnaire. Self-monitoring procedures were explained, emphasizing the importance of accurate, and continuous monitoring. Subjects were informed that this was not a smoking cessation study, and that they were not being asked to alter their usual smoking behavior during the experiment. Subjects were told that their methadone dose might be changed at certain times during the study, but would be maintained within a therapeutic range (SO-SO mg). At each clinic visit throughout the study, self-monitoring cards were collected and reviewed by the research assistant. CO measures were taken. Subjects earned a small weekly payment ($15) for their compliance with study requirements.
J. M.
Schmitz
Table I Characteristics Participant
209 238 245 267 454 ‘Maintenance bFagerstr6m
ez al. /Drug
and
of the subject Sex
M M M M F
Alcohol
Depend.
34 (1994)
239
237-242
sample
Age (year)
Race
44 31 40 38 30
B W B I-1 W
(year)
Methadone dose (mg)”
Smoking onset (age)
(cpd)
(ppm)
FTQb score
12 14 12 14 10
80 50 50 80 50
20 I1 19 16 15
25 40 16 40 30
28 32 21 30 29
8 8 6 x 9
Education
Smoking
CO level
rate
dose at start of study. Tolerance Questionnaire.
S-209 301
S-238 30 25 20 15 10 5 0
8asee
80
50
80
Base&km
50
50
80
50
80
50
80
50
S-267 40 r 35 30 25 20 15 10 5
OL’ Bas&ttne
o-
50
80
50
80
Ba.seseine 80
group
5. S-245 30
45. ‘u56. 30.
I _,1,’
I,’
25 2015 -
25-M' 20
10 .-
15 10
5-
50
~aaetine 50
80
50
Methadone
Fig. I. Mean number
of cigarettes
50
50
80
smoked
80
dosage (mg)
per day as a function
of methadone
dose condition,
240
J.M. Schmir;
3. Results
et al. /Drug
and Alcohol Depend. 34 (1994) 237-242
jects repeated measures analysis of variance comparing
3.1. Self-monitoring
the daily smoking rates of each subject during three phases of baseline self-monitoring: early (day l-5), middle (day 6-lo), and late (day 11-14). The number of cigarettes smoked per day was not found to significantly change over baseline phases, F(2,8) = 1.373, NS.
compliance
Compliance was calculated for each subject in terms of the number of completed self-monitoring cards returned divided by the total number of days in the study. Percentages were above 90% in four subjects (209, 245, 267, 454) and 78% in subject 238. Reactive effects of self-monitoring were assessed by a treatment by sub-
3.2. Smoking changes across methadone conditions The difference in group mean daily smoking when
s-238
s-209 . m=50 + m=80
S-267
b-4
4-8
8-12
12-16
16-20
20-24
S-245 0.5 n
0.4. 0.3. 0,2
.
-
. _,x
c.-
_.,
.\
O.lo-
m-80
. m=50
\\ O-4
4-8
8-12
\Ljc_.-
2
12-16 16-20 20-24
Time interval Fig. 2. Proportion
of total-day
smoking
during
successive
4-h time intervals
following
methadone
ingestion
J.M.
Schmitt
et al. /Drug
and Alcohol
Depend.
34 (1994)
237-242
methadone dose was 50 mg (mean = 24.5, S.D. = 9.8) and 80 mg (mean = 27.3, SD. = 10.8) was significant, F( 1,4) = 12.11, P < 0.006. As shown in Fig. 1, data from three subjects (209,267,454) tit the dose effect protile, with increases (decreases) in mean cigarettes smoked per day greater than 2 standard errors. Daily smoking rate for subject 245 increased significantly over time, but unrelated to methadone dose. Subject 238 reduced overall cigarette consumption during the study by 12 cigarettes per day. When interviewed at the conclusion of participation in the study, this subject reported efforts to quit smoking in response to a recent worksite no-smoking policy. 3.3. CO data Correlations were examined between expired air carbon monoxide levels and daily smoking rate. Group mean CO levels were higher in the 80 mg (mean = 25.8, SD. = 7.2) than 50 mg (mean = 23.5, S.D. = 8.4) methadone condition, yet this difference was not significant F(1,4) = 2.03, P = 0.15. None of the individual subject correlations were statistically significant (r values = 0.08 to 0.16). These nonsignificant findings most likely reflect a methodological shortcoming in collecting CO readings early in the day (i.e., 8:00 a.m.). While morning carbon monoxide measurements are sensitive to cigarette smoking, they provide less quantitative information about the magnitude of daily exposure than do afternoon or evening levels (Benowitz, 1983). 3.4. Patterns ofsmoking within days The within-day temporal relationship between methadone and smoking was examined by calculating the means of the daily proportion of smoking during successive 4-h time intervals following methadone ingestion for low and high dose conditions (Fig. 2). For three subjects (238, 267, 454) the highest percentage of total smoking occurred within 4 h following methadone, then gradually declined over the day. Subject 245 smoked about 25% of his total number of cigarettes within 4 h following methadone, with a relatively constant smoking rate throughout the remainder of the day. For subject 209, smoking reached its peak within 4-8 h following methadone. In general, methadone dose (50 mg vs. 80 mg) did not appear to produce differences in the pattern of these results. 4. Discussion
The present study demonstrates that administration of methadone results in substantial, dose-related changes in rates of cigarette smoking by methadonemaintained smokers. For three of the five subjects, smoking rates increased then decreased as daily methadone dose (mg) was manipulated from 50 to 80 and 80 to 50, respectively. Self-reported changes in smoking be-
241
havior did not correspond with objective measures (i.e., expired air CO levels). Methadone ingestion, regardless of dosage, appeared to be a controlling event for cigarette smoking in three subjects whose proportion of total daily smoking was highest within the four hour interval after taking methadone. Data from the current study further support and extend human laboratory reports that methadone produces dose-related increases in cigarette smoking (Chait and Griffrths, 1984). To our knowledge, this is the first study to document this relationship in a non-laboratory setting, supporting the robustness of this drug interaction. Whereas Chait and Griffrths (1984) examined the acute dose-dependent effects of methadone on smoking, the present design permitted analyses of the stability of this relationship within and across days. Thus, it seems that when methadone dosage is adjusted (up or down) the associated change in smoking behavior, at least in some individuals, has a rapid onset and is maintained as long as the dose adjustment remains in effect. Self-monitoring appeared to be a useful approach for measuring natural smoking behavior in methadone maintenance patients. Patient acceptance and compliance with this procedure was generally high. This favorable response was due, in part, to the structured clinical research setting, which included frequent visits and contingent payment for study participation. Selfmonitoring has been a reactive procedure in smoking reduction studies (McFall and Hammen, 1971). In the present study, where subjects were not motivated to quit smoking, and where the response valence was neutral, reactive effects were not found. These findings must be considered with caution given certain liabilities in the study design and methodology. Perhaps most limiting is the potentially confounding effect of tiine of day at which methadone was given (8:00 a.m.). Higher smoking rates following methadone ingestion may have been influenced by time of day, as heavy a.m. smoking is typical of nicotine dependent smokers. As mentioned before, morning CO measurements may explain why no relationship between biochemical and self-reported smoking indices was found. An experimentally more rigorous test of the relationship between methadone and smoking might have been made, for example, by repeating the dose manipulation under conditions when methadone is dispensed at a later time of day. The pharmacological manipulation used in this study was unique and relatively powerful, given the constraints of the naturalistic context of an ongoing methadone maintenance setting. While letter codes were used to keep subjects blind to the actual dose of their daily medication, this procedure may not have adequately maintained blindness to dose changes, since the same letter-dose pairings were repeated across manipulations. Whether or not subjects were aware of dose changes
242
does not necessarily confound our main findings, since subjects were blind to study expectations and hypotheses regarding methadone and smoking behavior. Finally, while the predicted dose dependent effect was demonstrated in 3 of the 5 subjects, confidence in our interpretation of the data is reduced by the small sample size and between-subject variability. This study clearly provides a foundation and stimulus for further research. Cigarette smoking among methadone patients can be conceptualized as an integral part of polydrug dependence disorder. Investigation of this phenomenon is possible both within and outside of the laboratory. Increased cigarette consumption among clients maintained on higher dosages of methadone places these individuals at even greater risk for smokingrelated health problems. Methadone dosage and time of ingestion may have important implications in the development of smoking cessation programs for this high risk patient group. 5. Acknowledgments Preparation of this manuscript was supported by grant DA 06143-01 from the National Institute on Drug Abuse to John Grabowski. The authors thank the staff of the Addictive Behaviors Clinic and the Substance Abuse Research Center for their support and cooperation. 6. References Benowitz, N.L. (1983). Use of biological fluid samples in assessing tobacco smoke consumption. In: Measurement in the analysis and treatment of smoking behavior. NIDA Research Monograph 48 (Grabowski, J. and Bell, S. eds.), pp. 6-26. DHHS Publ. No. (ADM) 83-1285. U.S. Government Printing Office, Washington, DC. Burling, T.A. and Ziff, DC. (1988) Tobacco smoking: A comparison between alcohol and drug abuse inpatients. Addict. Behav. 13, 185-190.
J. M. Schtnitz
et al. /Drug
and Alcohol
Depend.
34 (1994)
237-242
Chait, L.D. and Griffiths, R.R. (1984) Effects of methadone on human cigarette smoking and subjective ratings. J. Pharmacol. Exp. Ther. 229, 636-640. DiFranza, J.R. and Guerrera, M.P. (1990) Alcoholism and smoking. J. Stud. Alcohol 51, 130-135. Fagerstrom, K.O. (1978) Measuring degree of physical dependence on tobacco smoking with reference to individualization of treatment. Addict. Behav. 3, 235-241. GriBiths, R.R., Bigelow, G.E. and Liebson, I. (1976) Facilitation of human tobacco self-administration by ethanol: A behavioral analysis J. Exp. Anal. Behav. 25, 279-292. Henningtield, J.E. and Griftiths, R.R. (1981) Cigarette smoking and subjective response: Effects of d-amphetamine. Clin. Pharmacol. Ther. 30, 497-505. Henningfield, J.E., Chait, L.D. and Grifftths, R.R. (1983) Cigarette smoking and subjective response in alcoholics: Effects of pentobarbital. Clin. Pharmacol. Ther. 33, 806-812. Hughes. J.R., Frederiksen, L.W. and Frazier, M. (1978) A carbon monoxide analyzer for measurement of smoking behavior. Behav. Therap. 9, 293-296. Istvan, 1. and Matarazzo, J.D. (1984) Tobacco, alcohol, and caffeine use: A review of their interrelationships. Psychol. Bull. 95, 301-326. McFall, R.M. and Hammen, C.L. (1971) Motivation, structure, and self-monitoring: Role of nonspecific factors in smoking reduction. J. Consul. Clin. Psychol. 37, 80-86. Mello, N.K., Mendelson, J.H., Sellers, M.L. and Kuehnle, J.C. (1980a) Effect of alcohol and marijuana on tobacco smoking. Clin. Pharmacol. Ther. 27, 202-209. Mello, N.K., Mendelson, J.H., Sellers, M.L. and Kuehnle, J.C. (1980b) Effects of heroin self-administration on cigarette smoking psychopharmacology. Psychopharmacology 67, 45-52. Rounsaville, B.J., Kosten, T.R., Weissman, M.M. and Kleber, H.D. (1985) Evaluating and Treating Depressive Disorders in Opiate Addicts. U.S. GPO, Washington, D.C.. Schuster, C.E., Lucchesi, B.R. and Emley, G.S. (1979) The effects of d-amphetamine, meprobamate, and lobeline on cigarette smoking behavior in normal human subjects. In: Cigarette Smoking as a Dependence Process. (Krasnegor, N.A., ed.). National Institute on Drug Abuse Research Monograph 23. National Institute on Drug Abuse, Rockville, Maryland. Spitzer, R.L. and Williams, J.B.W. (1986) Structured Clinical Interview for DSM-III-R - Personality Disorders (SCID-II, 5/l/86). Biometrics Research Department, New York State Psychiatric Institute, New York.
Drug and Alcohol
Dependence
34 (1994) 237-242
The effects of high and low doses of methadone on cigarette smoking Joy M. Schmitz *, John Grabowski,
Howard
Rhoades
Substance Abuse Reseurch Centre, Department of Psychiatry and Behuvioral Sciences. University of Texas Medical School. 1300 Mour.wnd .4 w Houston TX 77030, USA
(Accepted
27 July 1993)
Abstract The effect of methadone dose on the cigarette smoking of five methadone maintenance subjects was studied in a clinical setting. Following a two-week baseline period, daily doses of methadone were either increased (50-80 mg) or decreased (80-50 mg) every two weeks according to an A-B-A-B study design. Continuous self-monitoring was used to collect data on natural smoking behavior, and expired air carbon monoxide (CO) levels were measured at each clinic visit. The predicted methadone dose-related changes in smoking were found in three of the five subjects. Fine-grained analysis of self-monitoring records showed that the proportion of total daily smoking was highest within 4 h after taking methadone for three subjects. CO levels were not significantly associated with smoking rate. The results further support and extend previous reports that methadone may produce dose-related increases in smoking. No reactive effects of self-monitoring were observed, and compliance with this procedure was extremely high, supporting the usefulness of this method for assessing natural smoking behavior in this population. Key words:
Methadone
maintenance;
Tobacco
smoking;
Nicotine;
1. Intmduction
Tobacco dependence is common among users of other drugs, with smoking prevalence ranging from 85% to 100% in abusers of alcohol, opioids, and cocaine (Istvan and Matarazzo, 1984; Rounsaville et al., 1985; Burling and Ziff, 1988; DiFranza and Guerrera, 1990). The observed correlation between cigarette smoking and other drug use has been extended by laboratory studies demonstrating a more direct causal relationship between these variables, Acute administration of ethanol (Grifliths, Bigelow and Liebson, 1976; Mello et al., 1980a), heroin (Mello et al., 1980b), psychomotor stimulants (Schuster, Lucchesi and Emley, 1979; Henningfield and Griffiths, 1981), and sedatives (Henninglield, Chait and Grifliths, 1983) have produced increases in rates of cigarette smoking. Methadone itself has been shown to influence ciga-
* Corresponding author, University of Texas Mental Sciences Institute, 1300 Moursund, Houston, TX 77030, USA. 0 1994 Elsevier Science Ireland 0376-8716/94/$07.00 SSDI 0376-8716(93)0953-Y
Ltd. All rights
Self-monitoring
rette smoking in subjects maintained on methadone. Chait and Griffiths (1984), in the only published report to date, examined the interaction of acute methadone administration and smoking in five male methadone maintenance patients. Subjects participating in this controlled laboratory study were allowed to smoke ad libitum 90 min after receiving either a placebo, dextromethorphan, or one of three doses of methadone (0.5, 1.0, or 2.0 times their regular maintenance dose). It was found that methadone pretreatment produced substantial increases in cigarette smoking, level of carbon monoxide (CO), and subjective ratings of smoking satisfaction. This study represents the first attempt to use a nonlaboratory methodology to explore further the relationship between methadone administration and cigarette smoking. Five methadone maintenance patients recorded their daily smoking over an 8-week study period involving systematic methadone dose manipulations implemented under double blind conditions. The primary objectives were (a) to replicate the findings from laboratory studies in showing a dose-dependent relareserved
238
tionship between methadone and smoking, (b) to assess the extent to which natural smoking behavior could be recorded by self-monitoring procedures, and (c) to conduct a tine-grained analysis of the relationship between daily methadone ingestion and subsequent smoking for individual subjects. The study was reviewed and approved by the Committee for the Protection of Human Subjects of the University of Texas Health Science Center. 2. Methods 2.1. Subjects
Five patients enrolled in an outpatient methadone maintenance treatment research program at the University of Texas, Department of Psychiatry and Behavioral Sciences, Addictive Behaviors Clinic in Houston, Texas, participated in this study. To be eligible to participate, subjects had to (a) be regular cigarette smokers defined as at least 10 cigarettes per day; (b) have smoked for at least 12 months prior to the study; and (c) have a baseline expired-air carbon monoxide (CO) level of at least 15 parts per million (ppm). All had lengthy histories of opiate addiction. Subjects with significant medical or psychiatric disturbance were excluded. Characteristics of the study participants are presented in Table 1. Since this study focuses specifically on the relationship between methadone and nicotine, other concurrent drug use, with the exception of caffeine, was an exclusion criterion. Urinalysis results collected at our clinic during the 6-month study period preceding the present study were reviewed to determine regular use of other drugs or alcohol. Nine subjects were excluded from entry to the study by using this criterion. 2.2. Measurement
Daily smoking behavior was measured in two ways: by self-monitoring techniques and by expired air CO. Self-monitoring was implemented by instructing the subject to record each cigarette smoked according to the hour of the day. This information was recorded on small pre-printed cards cut to fit inside the cellophane wrapper of a cigarette package. In addition to recording cigarettes, subjects were instructed to indicate on the card the exact time of methadone ingestion each day. A Smoking History Questionnaire was used to assess smoking relevant variables (e.g., rate, duration) and included the Fagerstrom Tolerance Questionnaire (FTQ: Fagerstriim, 1978). Alveolar carbon monoxide (CO) levels were measured with the MiniCO Model 1000 portable ecolyzer (Catalyst Research Corporation, Owings Mills, MD). Subjects were not shown their CO values at the time of collection. Since cigarette smoking immediately before CO measurement is known to artificially inflate values (Hughes, Frederiksen and Frazier, 1978), subjects were asked to refrain from smoking at
J.M. Schmirz et al. /Drug
and Alcohol Depmd.
34 (1994) 237-242
least 30 min prior to collection. Before taking the CO test, time since the last cigarette was recorded. 2.3. Methadone dose manipulation
This study employed a within-subject A-B-A-B design to assess the influence of methadone dose on smoking behavior in the natural environment. Methadone dosage was either increased (SO-SO mg) or decreased (SO-SO mg) over successive 2-week intervals following a 2-week baseline period. For example, subjects on 50 mg during the 2-week baseline (A) were switched to the alternate dose (80 mg) for a 2-week period (B), and 2 weeks later, returned to the original dose (A). This increase-decrease cycle was repeated once, resulting in a total study duration of 8 weeks. Dose switches were made according to a 3-day, lo-mg dose increment (decrement) procedure. 2.4. Procedure
Subjects were recruited for this study during their final week of participation in a treatment study in which each patient was maintained on either 50 mg or 80 mg methadone (determined by random assignment) for the entire 6-month study period. This maintenance dose was set as the baseline condition for the present study. The 2-week baseline period allowed subjects to adapt to the self-monitoring and other study procedures. Study participants attended the clinic three times per week (Monday, Wednesday, and Friday) to ingest methadone delivered in a cherry syrup vehicle (Methadose@‘) under nursing supervision. Medicating times were 8:00 a.m. for all subjects. Individually packaged take-home doses of methadone were provided on remaining days. Dosages were letter-coded to provide some degree of blindness on the part of subjects, nurses, and research assistants regarding the experimental condition. Each methadone dose was associated with a specific letter. Subjects were not told of the coding system (i.e., that different letters signified different doses of methadone). At the initial clinic visit before the start of the study, patients signed the informed consent form and completed a smoking history questionnaire. Self-monitoring procedures were explained, emphasizing the importance of accurate, and continuous monitoring. Subjects were informed that this was not a smoking cessation study, and that they were not being asked to alter their usual smoking behavior during the experiment. Subjects were told that their methadone dose might be changed at certain times during the study, but would be maintained within a therapeutic range (SO-SO mg). At each clinic visit throughout the study, self-monitoring cards were collected and reviewed by the research assistant. CO measures were taken. Subjects earned a small weekly payment ($15) for their compliance with study requirements.
J. M.
Schmitz
Table I Characteristics Participant
209 238 245 267 454 ‘Maintenance bFagerstr6m
ez al. /Drug
and
of the subject Sex
M M M M F
Alcohol
Depend.
34 (1994)
239
237-242
sample
Age (year)
Race
44 31 40 38 30
B W B I-1 W
(year)
Methadone dose (mg)”
Smoking onset (age)
(cpd)
(ppm)
FTQb score
12 14 12 14 10
80 50 50 80 50
20 I1 19 16 15
25 40 16 40 30
28 32 21 30 29
8 8 6 x 9
Education
Smoking
CO level
rate
dose at start of study. Tolerance Questionnaire.
S-209 301
S-238 30 25 20 15 10 5 0
8asee
80
50
80
Base&km
50
50
80
50
80
50
80
50
S-267 40 r 35 30 25 20 15 10 5
OL’ Bas&ttne
o-
50
80
50
80
Ba.seseine 80
group
5. S-245 30
45. ‘u56. 30.
I _,1,’
I,’
25 2015 -
25-M' 20
10 .-
15 10
5-
50
~aaetine 50
80
50
Methadone
Fig. I. Mean number
of cigarettes
50
50
80
smoked
80
dosage (mg)
per day as a function
of methadone
dose condition,
240
J.M. Schmir;
3. Results
et al. /Drug
and Alcohol Depend. 34 (1994) 237-242
jects repeated measures analysis of variance comparing
3.1. Self-monitoring
the daily smoking rates of each subject during three phases of baseline self-monitoring: early (day l-5), middle (day 6-lo), and late (day 11-14). The number of cigarettes smoked per day was not found to significantly change over baseline phases, F(2,8) = 1.373, NS.
compliance
Compliance was calculated for each subject in terms of the number of completed self-monitoring cards returned divided by the total number of days in the study. Percentages were above 90% in four subjects (209, 245, 267, 454) and 78% in subject 238. Reactive effects of self-monitoring were assessed by a treatment by sub-
3.2. Smoking changes across methadone conditions The difference in group mean daily smoking when
s-238
s-209 . m=50 + m=80
S-267
b-4
4-8
8-12
12-16
16-20
20-24
S-245 0.5 n
0.4. 0.3. 0,2
.
-
. _,x
c.-
_.,
.\
O.lo-
m-80
. m=50
\\ O-4
4-8
8-12
\Ljc_.-
2
12-16 16-20 20-24
Time interval Fig. 2. Proportion
of total-day
smoking
during
successive
4-h time intervals
following
methadone
ingestion
J.M.
Schmitt
et al. /Drug
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methadone dose was 50 mg (mean = 24.5, S.D. = 9.8) and 80 mg (mean = 27.3, SD. = 10.8) was significant, F( 1,4) = 12.11, P < 0.006. As shown in Fig. 1, data from three subjects (209,267,454) tit the dose effect protile, with increases (decreases) in mean cigarettes smoked per day greater than 2 standard errors. Daily smoking rate for subject 245 increased significantly over time, but unrelated to methadone dose. Subject 238 reduced overall cigarette consumption during the study by 12 cigarettes per day. When interviewed at the conclusion of participation in the study, this subject reported efforts to quit smoking in response to a recent worksite no-smoking policy. 3.3. CO data Correlations were examined between expired air carbon monoxide levels and daily smoking rate. Group mean CO levels were higher in the 80 mg (mean = 25.8, SD. = 7.2) than 50 mg (mean = 23.5, S.D. = 8.4) methadone condition, yet this difference was not significant F(1,4) = 2.03, P = 0.15. None of the individual subject correlations were statistically significant (r values = 0.08 to 0.16). These nonsignificant findings most likely reflect a methodological shortcoming in collecting CO readings early in the day (i.e., 8:00 a.m.). While morning carbon monoxide measurements are sensitive to cigarette smoking, they provide less quantitative information about the magnitude of daily exposure than do afternoon or evening levels (Benowitz, 1983). 3.4. Patterns ofsmoking within days The within-day temporal relationship between methadone and smoking was examined by calculating the means of the daily proportion of smoking during successive 4-h time intervals following methadone ingestion for low and high dose conditions (Fig. 2). For three subjects (238, 267, 454) the highest percentage of total smoking occurred within 4 h following methadone, then gradually declined over the day. Subject 245 smoked about 25% of his total number of cigarettes within 4 h following methadone, with a relatively constant smoking rate throughout the remainder of the day. For subject 209, smoking reached its peak within 4-8 h following methadone. In general, methadone dose (50 mg vs. 80 mg) did not appear to produce differences in the pattern of these results. 4. Discussion
The present study demonstrates that administration of methadone results in substantial, dose-related changes in rates of cigarette smoking by methadonemaintained smokers. For three of the five subjects, smoking rates increased then decreased as daily methadone dose (mg) was manipulated from 50 to 80 and 80 to 50, respectively. Self-reported changes in smoking be-
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havior did not correspond with objective measures (i.e., expired air CO levels). Methadone ingestion, regardless of dosage, appeared to be a controlling event for cigarette smoking in three subjects whose proportion of total daily smoking was highest within the four hour interval after taking methadone. Data from the current study further support and extend human laboratory reports that methadone produces dose-related increases in cigarette smoking (Chait and Griffrths, 1984). To our knowledge, this is the first study to document this relationship in a non-laboratory setting, supporting the robustness of this drug interaction. Whereas Chait and Griffrths (1984) examined the acute dose-dependent effects of methadone on smoking, the present design permitted analyses of the stability of this relationship within and across days. Thus, it seems that when methadone dosage is adjusted (up or down) the associated change in smoking behavior, at least in some individuals, has a rapid onset and is maintained as long as the dose adjustment remains in effect. Self-monitoring appeared to be a useful approach for measuring natural smoking behavior in methadone maintenance patients. Patient acceptance and compliance with this procedure was generally high. This favorable response was due, in part, to the structured clinical research setting, which included frequent visits and contingent payment for study participation. Selfmonitoring has been a reactive procedure in smoking reduction studies (McFall and Hammen, 1971). In the present study, where subjects were not motivated to quit smoking, and where the response valence was neutral, reactive effects were not found. These findings must be considered with caution given certain liabilities in the study design and methodology. Perhaps most limiting is the potentially confounding effect of tiine of day at which methadone was given (8:00 a.m.). Higher smoking rates following methadone ingestion may have been influenced by time of day, as heavy a.m. smoking is typical of nicotine dependent smokers. As mentioned before, morning CO measurements may explain why no relationship between biochemical and self-reported smoking indices was found. An experimentally more rigorous test of the relationship between methadone and smoking might have been made, for example, by repeating the dose manipulation under conditions when methadone is dispensed at a later time of day. The pharmacological manipulation used in this study was unique and relatively powerful, given the constraints of the naturalistic context of an ongoing methadone maintenance setting. While letter codes were used to keep subjects blind to the actual dose of their daily medication, this procedure may not have adequately maintained blindness to dose changes, since the same letter-dose pairings were repeated across manipulations. Whether or not subjects were aware of dose changes
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does not necessarily confound our main findings, since subjects were blind to study expectations and hypotheses regarding methadone and smoking behavior. Finally, while the predicted dose dependent effect was demonstrated in 3 of the 5 subjects, confidence in our interpretation of the data is reduced by the small sample size and between-subject variability. This study clearly provides a foundation and stimulus for further research. Cigarette smoking among methadone patients can be conceptualized as an integral part of polydrug dependence disorder. Investigation of this phenomenon is possible both within and outside of the laboratory. Increased cigarette consumption among clients maintained on higher dosages of methadone places these individuals at even greater risk for smokingrelated health problems. Methadone dosage and time of ingestion may have important implications in the development of smoking cessation programs for this high risk patient group. 5. Acknowledgments Preparation of this manuscript was supported by grant DA 06143-01 from the National Institute on Drug Abuse to John Grabowski. The authors thank the staff of the Addictive Behaviors Clinic and the Substance Abuse Research Center for their support and cooperation. 6. References Benowitz, N.L. (1983). Use of biological fluid samples in assessing tobacco smoke consumption. In: Measurement in the analysis and treatment of smoking behavior. NIDA Research Monograph 48 (Grabowski, J. and Bell, S. eds.), pp. 6-26. DHHS Publ. No. (ADM) 83-1285. U.S. Government Printing Office, Washington, DC. Burling, T.A. and Ziff, DC. (1988) Tobacco smoking: A comparison between alcohol and drug abuse inpatients. Addict. Behav. 13, 185-190.
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