Nasal nicotine spray: a rapid nicotine delivery system

Psychopharmacology (1992) 108:512-518

Psychopharmacology © Springer-Vertag 1992

Nasal nicotine spray: a rapid nicotine delivery system G. Sutherland 1, M.A.H. Russell 1, J. Stapleton 1, C. Feyerabend 1, and O. Ferno 2 ICRF Health Behaviour Unit, Institute of Psychiatry, London SE5 8AF, U K 2 S :t Clemensgaten 14, S-25234 Helsingborg, Sweden Received January 22, 1992 / Final version March 11, 1992

Abstract. Plasma nicotine concentrations following administration by two types of nasal nicotine spray were compared in ten subjects. Absorption was particularly rapid during the first 2.5 rain, the average rise in blood nicotine concentrations during this time being 8.6 ng/ml for the two products, followed by a small further rise to an average peak increase of 10.5 ng/ml 5 rain after the dose of 2 mg nicotine base (mean 27.8 pg/kg). Despite a four-fold Cm~xvariation between subjects, the levels of individual subjects were fairly consistent across the two products. There were no significant differences between the two products in blood nicotine concentrations or cardiovascular responses, and the correlation between the AUCs from the two products was 0.68 (P=0.01). Eight subjects reported subjective feelings of lightheadedness or slight dizziness, which are not typical after slower absorption from nicotine gum or skin patches. Blood nicotine levels within the smoking range were soon built up with repeated doses, even in the subject with the least efficient nasal absorption. In a second study of ad libitum use under clinical conditions both products appeared sufficiently acceptable for therapeutic use as an aid to smoking cessation. There was no tendency to escalate to excessive use over 4 weeks, and blood nicotine concentrations in nine subjects averaged only 44% of their prior smoking levels. Only one subject had levels equivalent to prior smoking and possible reasons why this was not more common are discussed. Key words: Cigarette smoking - Nasal nicotine spray Nicotine pharmacokinetics -- Nicotine effects - Nicotine replacement treatment

Nicotine chewing gum has been a major advance in treatment for tobacco dependence and is now widely used in many countries. It reduces the severity of withdrawal effects (West 1984; Gross and Stitzer 1989), enCorrespondence to: G. Sutherland

hances success in short-term cessation, reduces relapse if use is not curtailed too soon, and roughly doubles longterm success rates compared with placebo and various psychological methods (Jarvis et al. 1982; Lam et al. 1987; Jarvis and Russell 1989). More importantly, its clinical success, its use as a research tool and the tendency for some smokers to transfer their dependence on cigarettes to dependence on the gum has provided new evidence that has increased understanding of smoking as a form of drug dependence (US Surgeon General's Report 1988). But the gum is only one of the potential methods of nicotine replacement and has certain disadvantages. Nicotine absorption from the gum is slow, and up to 30 min chewing is needed to release it all. There is also partial loss to the gastrointestinal tract through salivation and swallowing (Benowitz et al. 1987). People who use it rarely maintain blood nicotine concentrations much more than one-third of their normal smoking levels (Raw et al. 1980; McNabb 1984). Despite the clinical success of nicotine gum, it fails with many smokers. Long-term success rates seldom exceed 30%, even when the gum is used as an adjunct to intensive supportive treatments at specialised clinics. During the first few weeks of quitting, many smokers continue to experience unpleasant withdrawal symptoms while still using the gum and being encouraged to take as much of it as they want (West et al. 1987, 1989). It is not known whether better relief of withdrawal would be obtained from higher steady-state levels of nicotine replacement or whether a more rapid rate of nicotine absorption may also be important. As with the gum, transdermal absorption from nicotine skin patches is slow. Blood nicotine concentrations rise gradually to maximum levels at 6-8 h, which are then fairly well maintained for up to 16 h or more. Plateau levels from standard size 30 cm 2 patches (delivering 0.7-I.0 mg nicotine per h) average around 15 ng/ml. This is between a third and a half of the levels from usual smoking, but higher levels can easily be obtained from larger patches or by using more than one patch at a time (Dubois et al.

513

1989; Mulligan et al. 1990; Srivastava et al. 1991). Initial clinical trials with standard 30 cm 2 patches have been encouraging. The severity of withdrawal symptoms is significantly reduced and rates of short-term cessation are two to three times higher than those of placebo controls (Abelin et al. 1989; Tonnesen et al. 1991). Although no dose-response data are yet available on the patches, no acute subjective effects of light-headedness or slight euphoria have been reported. As with the gum, this is probably attributable to the slow rate of nicotine absorption, which gives time for the development of acute tolerance to these effects (Porchet et al. 1988; Russell 1988). In general, a nicotine boost of around 10 ng/ml in 10 min or less, as measured in mixed venous blood, is required to produce acute subjective effects (Russell 1988) and dose-related "liking" on the US Addiction Research Center's standardised scales (Henningfield et al. 1985). Besides tobacco smoke inhalation and intravenous injection, blood nicotine boosts of this order are produced by nasal snuff (Russell et al. 1980, 1981), oral snuff (Benowitz et al. 1988; Holm et al. 1992), subcutaneous injection (Russell et al. 1990) and nasal nicotine administration (Russell et al. 1983; Perkins et al. 1986). In view of its rapid absorption by the nasal route, Ove Ferno, some years ago, developed a device for delivering a droplet of nicotine solution into the nose. A 2 mg dose from this device produced a peak blood nicotine concentration averaging 14 ng/ml within 7.5 min. This is similar to the time taken to smoke a cigarette, and a subjective nicotine "buzz" was experienced by all subjects (Russell et al. 1983). Despite its potential clinical value as an aid to stopping smoking (Jarvis et al. 1987) and its use in experimental studies to deliver nicotine to nonsmokers (West and Jarvis 1986), there were some difficulties retaining the droplet in the nose during repeated self-administration in ambulant subjects (West et al. 1984). In terms of dosing accuracy and convenience, sprays or aerosols could be better devices for nasal administration. In pilot tests certain salts and solutions of nicotine were found to be well absorbed and sufficiently nonirritating for potential use in smoking cessation. We report here the results of preliminary studies to examine the blood nicotine profiles and acceptability of a nasal nicotine spray (NNS) and a nasal nicotine aerosol (NNA). Study 1 Ten healthy subjects (8 men, 2 women, mean age 36.7 years, range 26-55 years) were recruited among hospital staff and acquaintances. Five were cigarette smokers, two occasional cigar smokers, and three ex-smokers, who all gave informed consent. Two nasal nicotine devices were used on separate occasions for comparison. Each device delivered a metered dose of nicotine solution equivalent to 0.25 mg nicotine base per single "shot" or squeeze. By taking eight shots over 30 s subjects received a nasal dose of 2.0

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Fig. 1. Average plasma nicotine concentrations over time in ten subjects following 2 mg nicotine from a nasal nicotine spray (NNS) and nasal nicotine aerosol (NNA). (©--©) NNS; (e...e) NNA. Vertical bars show SDs

mg nicotine, an average of 27.8 gg/kg across all subjects. Through a plastic nozzle held in the nostril the nasal nicotine spray (NNS) device delivered a fixed dose of nicotine solution for each squeeze of a spray pump fitted to the mouth of a pocket-size multi-dose container bottle. Dose accuracy was within 5% (Johansson et al. 1991). The nasal nicotine aerosol (NNA) was a conventional pressurised metered-dose inhaler containing chlorofluorocarbon (CFC) propellant gases mixed with nicotine solution in a multi-dose canister. The canister was ftted in a plastic dispenser with an integral nozzle suitable for nasal delivery which was triggered by a single squeeze. All subjects completed tests on each device, tests on the NNA being done 3 months after those on the NNS which was available earlier. Procedures were the same on each occasion. During the week before testing subjects were given instructions and practised using the device. All tests were carried out after abstinence from smoking for at least 12 h (confirmed by expired air carbon monoxide of < 10 ppm). Blood samples were taken from a forearm or cubital vein via a butterfly cannula before and at 2.5, 5, 7.5, 10, 15, 20, 30, 45 and 60 rain after the 2 mg nicotine dose. The plasma was separated within 30 min and then frozen until analysis for nicotine (Feyerabend and Russell 1990). Heart rate and blood pressure were measured and recorded automatically from an upper arm cuff (Datascope Accutorr 1). The cumulative effect of repeated dosing was examined on a subsequent occasion in the two subjects who had shown the highest and lowest blood nicotine concentrations from the single dose of 2 mg NNS. On this second occasion, 2 mg NNS doses were taken at time 0,

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Table 1. Summary measures of plasma nicotine concentrations for 10 subjects using 2 mg of nasal nicotine spray (NNS) and nasal nicotine aerosol (NNA)

NNS-NNA differences Wilcoxon z P

NNS-NNA correlations Spearman r P

Plasma nicotine

NNS mean (SD)

NNA mean (SD)

Cmax (ng/ml) T.... (min) Rise (ng/ml) 0-2.5 rain Rise (ng/ml) 0-5.0 rain AUCo_6o (ng- min/ml)

12.4 (7.1) 6.0 (2.1) 8.7 (8.1)

11.7 (6.2) 10.8 (9.4) 8.5 (6.2)

0.66 1.50 -0.66

0.55 0.13 0.51

0.59 0.35 0.62

0.04 0.16 0.03

11.2 (7.3)

9.7 (6.8)

- 1.2

0.24

0.47

0.09

- 1.7

0.09

0.68

0.01

403

(135)

352

(133)

Baseline values excluded for AUC calculations

20 and 40 min, with blood sampled befbre and at 2.5, 5, 7.5, 10, 15 and 20 min after each of the three doses. Subjective and potential adverse effects were noted throughout all tests.

Results

Blood nicotine concentrations increased rapidly after nasal dosage, the mean concentrations over time reaching peaks of 11.8 ng/ml (SD=7.5) and 10.5 ng/ml (SD=7.0) 5 rain after NNS and NNA, respectively (Fig. 1). The nicotine absorption profiles of the two products were very similar and did not differ significantly (Table 1). However, curves from mean concentrations over time conceal much individual variation, and it has been argued that serial data of this kind should be displayed as in Fig. 2 (Matthews et al. 1990). The wide variation between subjects is clearly illustrated with C .... for example, ranging from 6.5 to 26.3 ng/ml after NNS and 5.6 to 22.5 ng/ml after NNA. Despite this variation between subjects, the nicotine levels of individual subjects were fairly consistent across the two products, as shown by the correlations in Table 1. Nicotine intake from N N A appeared to be slightly lower and the Tmax was more variable than after NNS, but these differences were not statistically significant. As shown in Fig. 3, the major changes in heart rate and BP were evident in the first 5 min and subsided gradually thereafter. On average the peak increase in heart rate at 5 min was 14.6 (SD=8.4) and 10.3 (SD = 5.5) bpm for the NNS and N N A respectively. The average increases in systolic and diastolic BP at 2.5 min were 7.8/9.9 mm Hg for NNS and 5.0/7.3 for NNA. There was a statistically significant quadratic component ( P < 0.01) to the trends over the first 20 min for heart rate but not for BP. There were no statistically significant differences in cardiovascular responses to the two products. The cumulative effects of repeated 2 mg doses of NNS in two subjects are shown in Fig. 4. These subjects had the highest (26.3 ng/ml) and lowest (6.5 ng/ml) Cmax blood nicotine among the ten subjects who received the single dose. Their maximal levels from repeated doses were 39.6 and 19.6 ng/ml at 7.5 and 5 min, respectively,

after the third dose. This indicates that levels in the smoking range can soon be built up even in those whose nasal absorption is relatively inefficient. All but two of the subjects experienced a subjective feeling of lightheadedness on each occasion. This was described variously as "a good buzz", "definite lightheadedness", "a heady feeling", "slight dizziness", "a swimming feeling", "a hit", or "feeling stoned". It came on rapidly within 2-3 min, built up and then waned after 10-15 min with one subject describing "coming down". One subject also described a "tingling in the hands and legs", while another had transient tinnitus. One subject (smoker) had no subjective effects on either occasion, while another (ex-smoker) was aware only of her "pounding heart". Palpitations were also experienced by a smoker and heart rate in both these subjects increased by more than 20 bpm. This smoker also felt slightly tense and tremulous on each occasion. One ex-smoker felt slight nausea and sweatiness after NNS and "cold fingers" after NNA, while one smoker felt nausea and dysphoria after N N A but not with NNS. Five subjects complained of local irritancy of NNS to the nose and watering eyes, whereas only three had this problem after NNA.

Study 2 To assess the acceptability of these nasal nicotine products as treatment aids for dependent smokers we conducted a pilot study among consecutive new attenders at the Maudsley Smokers Clinic, who would otherwise have received nicotine gum together with group therapy. We also wanted to gain clinical experience of the responses and problems from use of the products, to monitor any tendency for excessive use, and to reassure ourselves that subjects treated in the same group with different products would not be tempted out of curiosity to try each other's products, which would undermine "blindness" in any subsequent controlled trial. Twenty-six healthy smokers (8 men, 18 women, mean age 35.8 years, range 23-59) volunteered and gave informed consent to try one of the products as an aid to stop smoking, and no subjects refused to participate. Cigarette consumption averaged 24.0 per day (SD = 7.6)

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and expired air CO averaged 39.2 ppm (SD = t9.5). They were treated in two consecutive groups of 12 and 14 subjects and received our standard course of six group sessions over four weeks with subsequent follow-up (Hajek 1989). Those in the first group were randomised to NNS ( N = 6) or N N A (N = 6), while the second group received either NNS ( N = 7) or placebo spray (N = 7). This was because news had been received after planning the study that further development of N N A would be discontinued due to a Swedish ban on CFC based products. Both products were changed after the first study so that N N A delivered 0.5 mg nicotine per shot and NNS 1.0 mg nicotine per shot. Comparison of NNS and placebo in the second group was double-blind. Product use was ad libitum, with instructions given designed to avoid exceeding 5 mg in 1 h and 40 mg nicotine per day. For comparison with peak blood nicotine concentrations I-2 man after a cigarette measured at initial assessment, peak levels 5-10 min after a 1 mg nasal dose were measured in abstinent subjects (expired-air CO < 10 ppm) who were still using an active product at the time of the last group session at 4 weeks.

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Results

Altogether eight subjects relapsed to smoking and decided to drop out early. None cited difficulty with the product as a reason. Of the 18 who had stopped smoking for at least the week preceding the last group session at 4 weeks, 14 were on an active product and 4 on placebo• Subjects required careful instructions, encouragement and reassurance to persist and use the products sufficiently to acquire the technique and overcome problems of local irritancy. These problems appeared to be of a similar order to those encountered with getting used to nicotine gum. N N A was easier to use and less irritating than NNS and its placebo, and through evaporation of the gaseous vehicle was less likely to run out of the nose or through to the throat. Daily use of active products averaged about 17 shots per day and was maintained at this level over four weeks. Use of placebo, in contrast, averaged 13 shots per day at 2 days and dwindled rapidly to less than 1 shot per day at 4 weeks. No adverse effects were encountered that were cause for clinical concern. Blood samples were obtained from 9 of the 13 abstinent subjects still using an active product at four weeks (one abstinent subject had stopped using the spray).

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Compared with their mean peak blood nicotine level of 32.2 ng/ml (SD = 11.6) from smoking prior to treatment, the mean peak level from ad lib nasal dosage was 14.1 ng/ml (SD= 11.6), i.e. 44% of the smoking level. The average plasma cotinine concentration was likewise 40 % of the smoking level. Only one subject had levels equivalent to those of prior smoking. Finally, there were no known instances in either group of unauthorised use of another person's spray. Doubleblind conditions were preserved in the second group. Randomisation within groups is therefore feasible in future trials.

Discussion

The data confirmed the rapid absorption of nicotine by the nasal route. The pattern was similar in the two products tested. Absorption was particularly rapid in the first 2.5 min, the average rise in blood nicotine concentrations during this time being 8.6 ng/ml averaged over the two products, followed by a small further rise to an average increase of 10.5 ng/ml 5 rain after starting dosage. This is more rapid than that of the earlier nasal nicotine droplet (Russell et al. 1983) but similar to the aerosol used by Perkins et al. (1989). It is also somewhat faster than nicotine absorption from oral snuff (Benowitz et al. 1988; Holm et al. 1992), although similar to that of nasal snuff (Russell et al. 1980, 1981). Despite the consistency within subjects, there was marked variation between subjects in the blood nicotine levels following dosage. Variations in technique apparently make little difference to the site of deposition in the nose. However good the technique, some 80% of the dose of a nasal aerosol is deposited in the anterior one-third of the nose and penetration is negligible beyond the narrow point known as the "nasal valve" (Newman et al. 1987). In any case, site of placement by micropipette seems to make little difference to nicotine absorption (Johansson et at. 1991). A fair degree of individual variation in blood nicotine concentrations is evident even after intravenous dosage standardised for body weight (Benowitz et al. 1982; Feyerabend et al. 1985) and similar dispositional factors following absorption may have accounted for much of the variation between individual subjects in the present study.

517 As expected the rate o f absorption was sufficient to produce the typical acute subjective effects o f nicotine, such as slight dizziness and lightheadedness, which are seldom experienced during slower absorption from nicotine gum or skin patches. However, there were no placebo controls so the possibility of a placebo response cannot be excluded. The sharp increases in heart rate and blood pressure were similar to those o f the placebocontrolled nasal aerosol study of Perkins et al. (1986). The subjective effects and cardiovascular responses were also similar to those from a cigarette smoked after overnight abstinence (Roth et al. 1944; Herxheimer et al. 1967; West and Russell 1987). However, subjective effects o f this kind are subject to acute tolerance and are seldom experienced after cigarettes smoked during the course of a typical smoking day (West and Russell 1987). Their role as reinforcers or motives for smoking is therefore questionable and their underlying mechanisms are unknown. Although the mean blood nicotine boost o f 10.5 ng/ml in 5 min is somewhat less than that from the first cigarette o f the day (Russell et al. 1983; Benowitz et al. 1988), it is similar to the average boost per cigarette during usual smoking thoughout the day (Russell et al. 1981). Furthermore, our data show that with repeated doses of NNS, blood nicotine levels comparable to those from smoking were obtained within the first hour, even in the case o f the subject whose nasal absorption was least efficient. In view of the 1--4 h (mean 2 h) elimination half-life of nicotine (Benowitz et al. 1982; Feyerabend et al. 1985), it is difficult to understand how Perkins et al. (1989) failed to find a cumulative effect from repeated use at 20 min intervals o f their nasal nicotine aerosol. Our results show that nasal nicotine by spray or aerosol is absorbed sufficiently rapidly to produce positive subjective effects similar to those from smoking, and that with repeated ad libitum use any desired blood level o f nicotine could easily be obtained, within or above the smoking range. Subjects in the pilot clinical study soon adapted to initial problems with local irritancy and both products appeared sufficiently acceptable for everyday clinical use. However, as with nicotine gum, careful instructions and support in the early stages are likely to be necessary to secure good compliance. Unlike the placebo, use o f the active products was maintained at a fairly constant level throughout the 4 weeks of treatment and suggests that nicotine per se served some functions for the subjects. The lack of any tendency to escalate to excessive use was reassuring. Nicotine intake averaged no more than 40M5% o f the levels from prior smoking. Average daily use of the products was less than one quarter of the recommended maximum. Higher blood nicotine levels could easily have been achieved if the subjects had so desired. Their failure to take higher doses suggests that at the levels reached the products had provided all the withdrawal relief and positive reinforcement o f which they were capable, and that higher nicotine intake by this route either offers no further reinforcment or may even be aversive. What is the missing ingredient that prevented nasal administration up to smoking levels? One possibil-

ity is the lack o f bolus effects from the transient high nicotine boli that follow each inhaled puff o f cigarette smoke and exceed 100 ng/ml when measured in arterial blood (Isaac and Rand 1969; Rand 1989). On the other hand, subjects may have inadvertently rationed themselves through fear of toxic effects or becoming addicted. We were cautious in this trial and could in future be firmer about encouraging more liberal NNS use. In conclusion, we have demonstrated the rapid absorption of nicotine from a nasal nicotine spray (NNS) which is sufficiently safe and acceptable for clinical use as an aid to stopping smoking. Placebo-controlled trials are currently in progress with a product similar to the NNS used in our second study. It is not known to what extent the rate of absorption or steady-state blood nicotine levels are important for success in nicotine replacement therapy. Comparison o f NNS and nicotine skin patches will in due course provide some answers. Their use in experimental studies should help to increase understanding o f the pharmacokinetic and pharmacodynamic interactions that underly the complex pharmacology o f nicotine.

Acknowledgements. We thank the Medical Research Council for financial support. Dr. Urbain Sawe of Kabi Pharmacia Therapeutics AB, Helsingborg, Sweden, and Mr. C Carling of Astra Draco AB, Lund, Sweden, gave helpful advice and we thank their companies for providing the nasal nicotine products.

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518 Holm H, Jarvis MJ, Russell MAH, Feyerabend C (1992) Nicotine intake and dependence in Swedish snuff takers. Psychopharmacology 108:507-511 Isaac PF, Rand MJ (1969) Blood levels of nicotine and physiological effects after inhalation of tobacco smoke. Eur J Pharmacol 8: 265-283 Jarvis M J, Russell MAH (1989) Treatment for the cigarette smoker. Int Rev Psychiatry 1 : 139-147 Jarvis MJ, Raw M, Russell MAH, Feyerabend C (1982) Randomised controlled trial of nicotine chewing gum. BMJ 285: 537-540 Jarvis M J, Hajek P, Russell MAH, West RJ, Feyerabend C (1987) Nasal nicotine solution as an aid to cigarette withdrawal: a pilot clinical trial. Br J Addict 82:983-988 Johansson CJ, Olsson P, Bende M, Carlsson T, Gunnarsson PO (1991) Absolute bioavailability of nicotine applied to different nasal regions. Eur J Pharmacol 41:585-588 Lam W, Sze PC, Sacks HS, Chalmers TC (1987) Meta-analysis of randomised controlled trials of nicotine chewing gum. Lancet ii: 27-29 Matthews JNS, Altman DG, Campbell MJ, Royston P (1990) Analysis of serial measurements in medical research. BMJ 300:230-235 McNabb ME (1984) Chewing gum for 3 months: what happens to plasma nicotine levels? Can Med Assoc J 131:589-592 Mulligan SC, Masterson JG, Devane JG, Kelly JG (1990) Clinical and pharmacokinetic properties of a transdermal nicotine patch. Clin Pharmacol Ther 47:331-337 Newman SP, Moren F, Clarke SW (1987) The nasal distribution of metered dose inhalers. J Laryngol Otol 101 : 127-132 Perkins KA, Epstein LH, Jennings JR, Stiller R (1986) The cardiovascular effects of nicotine during stress. Psychopharmacology 90: 373-378 Perkins KA, Epstein LH, Stiller RL, Marks BL, Jacob RG (1989) Chronic and acute tolerance to the heart rate effects of nicotine. Psychopharmacology 97: 529-534 Porchet HC, Benowitz NL, Sheiner LB (1988) Pharmacodynamic model of tolerance: application to nicotine. J Pharmacol Exp Ther 244:231-236 Rand MJ (1989) Neuropharmacological effects of nicotine in relation to cholinergic mechanisms. In: Nordberg A, Fuxe K, Holmstedt B, Sundwall A (eds) Progress in brain research 79. Elsevier, Amsterdam, pp 3-11

Raw M, Jarvis MJ, Feyerabend C, Russell MAH (1980) Comparison of nicotine chewing gum and psychological treatments for dependent smokers. BMJ 281:481-482 Roth GM, McDonald JB, Sheard C (1944) The effect of smoking cigarettes. JAMA 125:761-767 Russell MAH (1988) Nicotine replacement: the role of blood nicotine levels, their rate of change, and nicotine tolerance. In: Pomerleau OF, Pomerleau CS (eds) Nicotine replacement: a critical evaluation. Liss, New York, pp 63-94 Russell MAH, Jarvis M J, Feyerabend C (1980) A new age for snuff?. Lancet i: 474-475 Russell MAH, Jarvis MJ, Devitt G, Feyerabend C (1981) Nicotine intake by snuff users. BMJ 283:814-817 Russell MAH, Jarvis MJ, Feyerabend C, Ferno O (1983) Nasal nicotine solution: a potential aid to giving up smoking. BMJ 286 : 683-684 Russell MAH, Jarvis MJ, Jones G, Feyerabend C (1990) Nonsmokers show acute tolerance to subcutaneous nicotine. Psychopharmacology 102:56-58 Srivastava ED, Russell MAH, Feyerabend C, Masterson JG, Rhodes J (1991) Sensitivity and tolerance to nicotine in to smokers and nonsmokers. Psychopharmacology 105:63-68 Tonnesen P, Norregaard J, Simonsen K, Sawe U (1991) A doubleblind trial of a 16-hour transdermal nicotine patch in smoking cessation. N Engl J Med 325 : 311-315 US Department of Health and Human Services (1988) Nicotine addiction: a report of the Surgeon General. Washington, DC West RJ (1984) Psychology and pharmacology in cigarette withdrawal. J Psychosom Res 28:379-386 West R J, Jarvis MJ (1986) Effects of nicotine on finger tapping rate in non-smokers. Pharmacol Biochem Behav 25:727-731 West RJ, Russell MAH (1987) Cardiovascular and subjective effects of smoking before and after 24 h abstinence from cigarettes. Psychopharmacology 92 : 118-121 West RJ, Jarvis MJ, Russell MAH, Feyerabend C (1984) Plasma nicotine concentrations from repeated doses of nasal nicotine solution. Br J Addict 79:443~445 West RJ, Hajek P, Belcher M (1987) Time course of cigarette withdrawal symptoms during four weeks of treatment with nicotine chewing gum. Addict Behav 12:199-203 West R, Hajek P, Belcher M (1989) Time course of cigarette withdrawal symptoms while using nicotine gum. Psychopharmacology 99:143-145