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Transdermal administration of nicotine
Drug and Alcohol Dependence, 13 (1984) 20!3-213 Elsevier Scientific Publishers Ireland Ltd.
TRANSDERMAL
ADMINISTRATION
209
OF NICOTINE
J.E. ROSE, M.E. JARVIK and K.D. ROSE Department of Psychiatry, Centre for Health Sciences, Westwood Plaza, Los Angeles, CA 90024 (U.S.A.)
University of California, 760
(Received January 25th, 1984) SUMMARY
The physiological response to nicotine topically applied to the skin was measured in an adult male volunteer. Nicotine base (9 mg) was applied in a 30% aqueous solution to intact skin on the underside of the forearm. Salivary nicotine, heart rate and blood pressure were monitored for 12 h after application of the nicotine. Within 30 min a significant level of nicotine was detected in the saliva (50 ng/ml), pulse had risen by 15 beats/min and systolic blood pressure had risen 10 mmHg. Nicotine levels remained elevated for 2 h and were comparable to levels of nicotine produced by cigarette smoking. Because previous research has shown nicotine to suppress smoking behavior, it may be fruitful to examine transdermal administration of nicotine as a smoking reduction and cessation aid. Key words: Nicotine - Cigarette smoking - Transdermal administration Nicotine has been shown to be a major pharmacological component in tobacco which contributes to the maintenance of cigarette smoking [l-3]. Consequently, one experimental approach to smoking reduction and cessation has been to substitute pure nicotine for the nicotine obtained from tobacco. Nicotine substitution would reduce the intake of carcinogens present in smoke particulates, as well as dangerous volatile substances such as hydrogen cyanide, carbon monoxide and formaldehyde [ 41. The effects of oral, intravenous and buccal routes of administration of nicotine have been studied, and all have been found to suppress cigarette smoking to some degree. However, when applied therapeutically these routes of administration suffer from significant problems, discussed below. The present study examined the feasibility of the transdermal route of administration of nicotine. The transdermal route has been successfully employed in administering therapeutic drugs such as nitroglycerin and scopolamine, allowing for a sustained release of drug and more accurate control of dose than oral administration [ 5,6]. In addition, it has been known for some time that nicotine is readily absorbed through intact skin, 0376-8716/84/$03.00 o 1984 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
210
and sometimes leads to the ‘green tobacco sickness’ experienced by tobacco harvesters when touching wet tobacco leaves with bare hands 171. In order to explore the possibility of therapeutic transdermal administration of nicotine, the present study measured, under controlled conditions, the systemic levels of nicotine achieved by topical application to the skin, METHOD Subjects
The subject (one of the experimenters) was an adult male (age 31) in good health, who did not smoke or consume any tobacco products. Procedure
The subject entered the lab at 10 : 00 having abstained from caffeine and alcohol for 12 h. After baseline readings of pulse and blood pressure (15 min and immediately prior to nicotine administration), 9 mg of nicotine (base) was applied in a 305%aqueous solution to the underside of the left forearm, covered by a thin layer of polyethylene (to prevent evaporation) and taped in place. Selection of the 9 mg dose was based on pilot work suggesting that this amount was required to produce reliable physiological effects. Systemic nicotine levels were noninvasively monitored in saliva, which was collected by having the subject expectorate into a vial at the following time points with respect to nicotine a~~~~tion: -15,0,15,30,60,90,120,189, 240, 360, 480 and 720 min. Because the subject was not a smoker, the possibility of direct contamination of the saliva by nicotine in smoke was ruled out. Saliva pH was measured with a Corning Model 12 pH meter to kO.1 units, and the samples were sent to the Clinical Psychopharmacology Laboratory at the Veterans Administration Medical Center Sepulveda for biochemical analysis (in duplicate). The accuracy of the high pressure liquid chromatography technique employed was +lO%. Pilot work with the same subject had demonstrated that saliva nicotine levels were roughly 75 ng/ml2 h after topical admonition of 9 mg nicotine. Physiolo~c~ measures were also taken as an index of nicotine’s effects. For reasons of expedience, the experimenter took his own physiological readings. Radial pulse was counted for two successive minutes at each time point, and the values averaged; variability was +2 beatsimin. Systolic and diastolic blood pressure were also measured twice at each time point, with a reliability off 5 mmHg. All readings were taken with the subject seated at rest. RESULTS Figure 1 illustrates the time course of nicotine levels in the subject’s saliva. Within 30 min salivary nicotine rose to a level of 50 ng/ml and reached
211 PtW9loLoWAL
2
RESFONE lo
4
6
TRANSDERMALNKZOTINE
t3
10
12
Fig- 1. Time course of saliva nicotine concentration, heart rate, systolic and diastolic blood pressure following topical application of 9 mg nicotine base to the skin. Error bars denote the range of variability in the two measures taken at each point. The arrow indicates when the nicotine was applied. a peak (at 90 min) of 85 ng/ml, levels comparable to those produced by cigarette smoking [ 81. The relative concen~tions of nicotine in saliva and blood is pH dependent, stemming from the acid-base equilibrium of nicotine. Because salivary pH remained near 7 over the course of the study, the expected ratio of saliva to blood nicotine concentrations was approx. 2 : 1 191. The increase in salivary nicotine was maintained for over 2 h, after which it gradually declined and by 12 h did not differ from baseline. Although baseline nicotine levels were very low, they may have been nonxero due to the passive exposure of the subject to trace amounts of cigarette smoke or nicotine prior to the start of the experiment. The physiological measures are plotted below the nicotine time curve for comparison. Heart rate increased substantially during the first 30 mm and reached a level commonly achieved by smokers after consuming the first cigarette of the day [ 10 J , Systolic and diastolic blood pressure also increased, and generally the physiological indices paralleled the nicotine levels observed in saliva (r = 0.63, 0.88, 0.57, P < 0.05, for heart rate, systolic and diastolic
212
blood pressure, respectively). Interestingly, heart rate and systolic blood pressure seemed to remain elevated for a short time after nicotine levels had declined to near baseline levels. This could have been due to the greater sensitivity of these responses to low concentrations of nicotine or to hormonal effects triggered by nicotine. DISCUSSION
The present study has confirmed that it is possible to produce significant systemic levels of nicotine by topical application to the skin, and has revealed some features of the time course of transdermally applied nicotine. The absorption of nicotine was accompanied by marked physiological responses (increased pulse and blood pressure) similar to those observed in smokers after the first cigarette of the day. In the absence of a control for time of day, we cannot conclude with certainty that the cardiovascular effects were due to absorbed nicotine; however, the high correlations between saliva nicotine levels and the physiological measures suggest that they were induced by nicotine. The effects in a nonsmoking subject may have been greater; however, Rosenberg et al. [ 111 have argued that even in habitual smokers little tolerance remains to the cardio-acceleratory effects of smoking after overnight abstinence. Although the transdermal nicotine was not absorbed as rapidly as in smoke from a cigarette, the sustained elevation in systemic nicotine levels suggests that it may be a promising strategy for reducing craving and smoking withdrawal symptoms. Since the half life of nicotine varies widely between individuals [12], the amount of nicotine and the vehicle in which it is applied may have to be individually adjusted to optimize its effects and extend its duration of action. Transdermal nicotine would have several potential advantages over other routes of administering nicotine. Nicotine injected intravenously or subcutaneously has been shown in some experimental studies to suppress smoking [13,14] but it is not practical as a smoking cessation treatment. Oral capsules have a great uncertainty in dose, since nicotine is efficiently removed from the blood on passing through the liver. In contrast, transderma1 and buccal absorption bypass the portal circulation. Nicotine chewing gum, which exploits the buccal route of administration, has been proposed as a practical smoking cessation aid [ 151. However, the direct contact of nicotine with the lining of the oral cavity and esophagus often produces aversive effects, such as bad taste, heartburn, nausea and hiccups [ 161. Transdermal nicotine would eliminate these side effects. Further, transdermal nicotine would have the potential of requiring much less frequent application than the gum, and could even sustain levels during sleep, if desired. Because cigarette craving in the morning is presumably due to low nicotine levels, this could be a substantial advantage. The reduction of side effects and less frequent need for application would likely increase compliance with treatment over that with the gum.
213
Whether transdermal nicotine is indeed a fruitful smoking reduction and cessation tool will be answered by future research with smokers to determine whether cigarette craving and withdrawal symptoms can be alleviated by this technique. ACKNOWLEDGEMENTS
This research was supported in part by UCLA Biobehavioral Research Support Grant No. RR5756, and by the Medical Research Service of the Veterans Administration. The authors would like to thank Kenneth Tachiki, Ph.D., Veterans Administration Medical Center Sepulveda, for performing the nicotine assays on samples collected in this study. REFERENCES 1 A.K. Armitage, G.H. Hall and C.F. Morrison, Nature, 217 (1968) 331. 2 M.E. Jarvik, in: W.L. Dunn (Ed.), Smoking Behavior: Motives and Incentives, V.H. Winston & Sons, Inc., Washington, DC, 1973, pp. 33-49. 3 J.E. Rose, M.E. Jarvik and S. Ananda, Pharmacol. Biochem. Behav., (1984) in press. 4 M.R. Guerin, in: G.B. Gori and F.G. Bock (Eds.) Banbury Report, Cold Spring Harbor Laboratory, New York, 1980, pp. 191-204. 5 M.E. McCauley, J.W. Royal, J.E. Shaw and L.G. Schmitt, Aviat. Space, Environ. Med., 50 (11) (1979) 1108. 6 J.O. Parker, R.J. Augustine, J.P. Burton, R.O. West and P.W. Armstrong, Am. J. Cardiol. 38 (1976) 162. 7 S.H. Gehlbach, W.A. Williams and J.I. Freeman. Arch. Environ. Health, March/April (1979) 111. 8 C. Feyerabend, T. Higenbottam and M.A.H. Russell, Br. Med. J., 284 (1982) 1002. 9 E.F. Domino, in: A. Remond and C. Izard (Eds.), Electrophysiological Effects of Nicotine, Elsevier/North-Holland, Amsterdam, 1979, 133-146. 10 R.M. Stephens, Addict. Behav., 2 (1977) 1. 11 J. Rosenberg, N.L. Benowitz, P. Jacob and K.M. Wilson, Clin. Pharmacol. Ther., 28 (4) (1980) 517. 12 N.L. Benowitz, P. Jacob, III, R.T. Jones and J. Rosenberg, J. Pharmacol. Exp. Ther., 221 (2) (1982) 368. 13 L.M. Johnston, Lancet, 2 (1942) 742. 14 B.R. Lucchesi, C.R. Schuster and A.B. Emley, Clin. Pharmacol. Ther., 8 (1967) 789. 15 P. Ohlin and H. Westling, in: R.G. Richardson (Ed.), Proceedings of the Second World Conference on Smoking and Health, 1972, pp. 171-174. 16 M.A.H. Russell, M. Raw and M.J. Jarvis, Br. Med. J., 280 (1980) 1599.
TRANSDERMAL
ADMINISTRATION
209
OF NICOTINE
J.E. ROSE, M.E. JARVIK and K.D. ROSE Department of Psychiatry, Centre for Health Sciences, Westwood Plaza, Los Angeles, CA 90024 (U.S.A.)
University of California, 760
(Received January 25th, 1984) SUMMARY
The physiological response to nicotine topically applied to the skin was measured in an adult male volunteer. Nicotine base (9 mg) was applied in a 30% aqueous solution to intact skin on the underside of the forearm. Salivary nicotine, heart rate and blood pressure were monitored for 12 h after application of the nicotine. Within 30 min a significant level of nicotine was detected in the saliva (50 ng/ml), pulse had risen by 15 beats/min and systolic blood pressure had risen 10 mmHg. Nicotine levels remained elevated for 2 h and were comparable to levels of nicotine produced by cigarette smoking. Because previous research has shown nicotine to suppress smoking behavior, it may be fruitful to examine transdermal administration of nicotine as a smoking reduction and cessation aid. Key words: Nicotine - Cigarette smoking - Transdermal administration Nicotine has been shown to be a major pharmacological component in tobacco which contributes to the maintenance of cigarette smoking [l-3]. Consequently, one experimental approach to smoking reduction and cessation has been to substitute pure nicotine for the nicotine obtained from tobacco. Nicotine substitution would reduce the intake of carcinogens present in smoke particulates, as well as dangerous volatile substances such as hydrogen cyanide, carbon monoxide and formaldehyde [ 41. The effects of oral, intravenous and buccal routes of administration of nicotine have been studied, and all have been found to suppress cigarette smoking to some degree. However, when applied therapeutically these routes of administration suffer from significant problems, discussed below. The present study examined the feasibility of the transdermal route of administration of nicotine. The transdermal route has been successfully employed in administering therapeutic drugs such as nitroglycerin and scopolamine, allowing for a sustained release of drug and more accurate control of dose than oral administration [ 5,6]. In addition, it has been known for some time that nicotine is readily absorbed through intact skin, 0376-8716/84/$03.00 o 1984 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
210
and sometimes leads to the ‘green tobacco sickness’ experienced by tobacco harvesters when touching wet tobacco leaves with bare hands 171. In order to explore the possibility of therapeutic transdermal administration of nicotine, the present study measured, under controlled conditions, the systemic levels of nicotine achieved by topical application to the skin, METHOD Subjects
The subject (one of the experimenters) was an adult male (age 31) in good health, who did not smoke or consume any tobacco products. Procedure
The subject entered the lab at 10 : 00 having abstained from caffeine and alcohol for 12 h. After baseline readings of pulse and blood pressure (15 min and immediately prior to nicotine administration), 9 mg of nicotine (base) was applied in a 305%aqueous solution to the underside of the left forearm, covered by a thin layer of polyethylene (to prevent evaporation) and taped in place. Selection of the 9 mg dose was based on pilot work suggesting that this amount was required to produce reliable physiological effects. Systemic nicotine levels were noninvasively monitored in saliva, which was collected by having the subject expectorate into a vial at the following time points with respect to nicotine a~~~~tion: -15,0,15,30,60,90,120,189, 240, 360, 480 and 720 min. Because the subject was not a smoker, the possibility of direct contamination of the saliva by nicotine in smoke was ruled out. Saliva pH was measured with a Corning Model 12 pH meter to kO.1 units, and the samples were sent to the Clinical Psychopharmacology Laboratory at the Veterans Administration Medical Center Sepulveda for biochemical analysis (in duplicate). The accuracy of the high pressure liquid chromatography technique employed was +lO%. Pilot work with the same subject had demonstrated that saliva nicotine levels were roughly 75 ng/ml2 h after topical admonition of 9 mg nicotine. Physiolo~c~ measures were also taken as an index of nicotine’s effects. For reasons of expedience, the experimenter took his own physiological readings. Radial pulse was counted for two successive minutes at each time point, and the values averaged; variability was +2 beatsimin. Systolic and diastolic blood pressure were also measured twice at each time point, with a reliability off 5 mmHg. All readings were taken with the subject seated at rest. RESULTS Figure 1 illustrates the time course of nicotine levels in the subject’s saliva. Within 30 min salivary nicotine rose to a level of 50 ng/ml and reached
211 PtW9loLoWAL
2
RESFONE lo
4
6
TRANSDERMALNKZOTINE
t3
10
12
Fig- 1. Time course of saliva nicotine concentration, heart rate, systolic and diastolic blood pressure following topical application of 9 mg nicotine base to the skin. Error bars denote the range of variability in the two measures taken at each point. The arrow indicates when the nicotine was applied. a peak (at 90 min) of 85 ng/ml, levels comparable to those produced by cigarette smoking [ 81. The relative concen~tions of nicotine in saliva and blood is pH dependent, stemming from the acid-base equilibrium of nicotine. Because salivary pH remained near 7 over the course of the study, the expected ratio of saliva to blood nicotine concentrations was approx. 2 : 1 191. The increase in salivary nicotine was maintained for over 2 h, after which it gradually declined and by 12 h did not differ from baseline. Although baseline nicotine levels were very low, they may have been nonxero due to the passive exposure of the subject to trace amounts of cigarette smoke or nicotine prior to the start of the experiment. The physiological measures are plotted below the nicotine time curve for comparison. Heart rate increased substantially during the first 30 mm and reached a level commonly achieved by smokers after consuming the first cigarette of the day [ 10 J , Systolic and diastolic blood pressure also increased, and generally the physiological indices paralleled the nicotine levels observed in saliva (r = 0.63, 0.88, 0.57, P < 0.05, for heart rate, systolic and diastolic
212
blood pressure, respectively). Interestingly, heart rate and systolic blood pressure seemed to remain elevated for a short time after nicotine levels had declined to near baseline levels. This could have been due to the greater sensitivity of these responses to low concentrations of nicotine or to hormonal effects triggered by nicotine. DISCUSSION
The present study has confirmed that it is possible to produce significant systemic levels of nicotine by topical application to the skin, and has revealed some features of the time course of transdermally applied nicotine. The absorption of nicotine was accompanied by marked physiological responses (increased pulse and blood pressure) similar to those observed in smokers after the first cigarette of the day. In the absence of a control for time of day, we cannot conclude with certainty that the cardiovascular effects were due to absorbed nicotine; however, the high correlations between saliva nicotine levels and the physiological measures suggest that they were induced by nicotine. The effects in a nonsmoking subject may have been greater; however, Rosenberg et al. [ 111 have argued that even in habitual smokers little tolerance remains to the cardio-acceleratory effects of smoking after overnight abstinence. Although the transdermal nicotine was not absorbed as rapidly as in smoke from a cigarette, the sustained elevation in systemic nicotine levels suggests that it may be a promising strategy for reducing craving and smoking withdrawal symptoms. Since the half life of nicotine varies widely between individuals [12], the amount of nicotine and the vehicle in which it is applied may have to be individually adjusted to optimize its effects and extend its duration of action. Transdermal nicotine would have several potential advantages over other routes of administering nicotine. Nicotine injected intravenously or subcutaneously has been shown in some experimental studies to suppress smoking [13,14] but it is not practical as a smoking cessation treatment. Oral capsules have a great uncertainty in dose, since nicotine is efficiently removed from the blood on passing through the liver. In contrast, transderma1 and buccal absorption bypass the portal circulation. Nicotine chewing gum, which exploits the buccal route of administration, has been proposed as a practical smoking cessation aid [ 151. However, the direct contact of nicotine with the lining of the oral cavity and esophagus often produces aversive effects, such as bad taste, heartburn, nausea and hiccups [ 161. Transdermal nicotine would eliminate these side effects. Further, transdermal nicotine would have the potential of requiring much less frequent application than the gum, and could even sustain levels during sleep, if desired. Because cigarette craving in the morning is presumably due to low nicotine levels, this could be a substantial advantage. The reduction of side effects and less frequent need for application would likely increase compliance with treatment over that with the gum.
213
Whether transdermal nicotine is indeed a fruitful smoking reduction and cessation tool will be answered by future research with smokers to determine whether cigarette craving and withdrawal symptoms can be alleviated by this technique. ACKNOWLEDGEMENTS
This research was supported in part by UCLA Biobehavioral Research Support Grant No. RR5756, and by the Medical Research Service of the Veterans Administration. The authors would like to thank Kenneth Tachiki, Ph.D., Veterans Administration Medical Center Sepulveda, for performing the nicotine assays on samples collected in this study. REFERENCES 1 A.K. Armitage, G.H. Hall and C.F. Morrison, Nature, 217 (1968) 331. 2 M.E. Jarvik, in: W.L. Dunn (Ed.), Smoking Behavior: Motives and Incentives, V.H. Winston & Sons, Inc., Washington, DC, 1973, pp. 33-49. 3 J.E. Rose, M.E. Jarvik and S. Ananda, Pharmacol. Biochem. Behav., (1984) in press. 4 M.R. Guerin, in: G.B. Gori and F.G. Bock (Eds.) Banbury Report, Cold Spring Harbor Laboratory, New York, 1980, pp. 191-204. 5 M.E. McCauley, J.W. Royal, J.E. Shaw and L.G. Schmitt, Aviat. Space, Environ. Med., 50 (11) (1979) 1108. 6 J.O. Parker, R.J. Augustine, J.P. Burton, R.O. West and P.W. Armstrong, Am. J. Cardiol. 38 (1976) 162. 7 S.H. Gehlbach, W.A. Williams and J.I. Freeman. Arch. Environ. Health, March/April (1979) 111. 8 C. Feyerabend, T. Higenbottam and M.A.H. Russell, Br. Med. J., 284 (1982) 1002. 9 E.F. Domino, in: A. Remond and C. Izard (Eds.), Electrophysiological Effects of Nicotine, Elsevier/North-Holland, Amsterdam, 1979, 133-146. 10 R.M. Stephens, Addict. Behav., 2 (1977) 1. 11 J. Rosenberg, N.L. Benowitz, P. Jacob and K.M. Wilson, Clin. Pharmacol. Ther., 28 (4) (1980) 517. 12 N.L. Benowitz, P. Jacob, III, R.T. Jones and J. Rosenberg, J. Pharmacol. Exp. Ther., 221 (2) (1982) 368. 13 L.M. Johnston, Lancet, 2 (1942) 742. 14 B.R. Lucchesi, C.R. Schuster and A.B. Emley, Clin. Pharmacol. Ther., 8 (1967) 789. 15 P. Ohlin and H. Westling, in: R.G. Richardson (Ed.), Proceedings of the Second World Conference on Smoking and Health, 1972, pp. 171-174. 16 M.A.H. Russell, M. Raw and M.J. Jarvis, Br. Med. J., 280 (1980) 1599.