This pilot study showed that using high doses of NRT in healthy pack-a-day or more smokers produced increasing side effects with increasing nicotine dose, however, they were generally tolerated, although 2 out of 25 subjects were excluded from using the 45 mg patch due to side effects. High dose NRT appeared to have little effect on physiological processes such heart rate, blood pressure, or weight, results that are concordant with an inpatient study (Zevin et al., 1998
). Furthermore, significant dose-related reductions in daily cigarette consumption can be achieved in an outpatient setting through high-dose nicotine therapy. Levels of reduction in cigarettes and CO were sustained even during the descending dose limb. Given the use of nicotine replacement, it is not surprising that reduction in daily smoking did not result in nicotine withdrawal and craving reduced significantly over time.
Although significant reductions were observed for number of cigarettes smoked and this reduction was dose-related, the extent of reduction at the highest dose was not as high as expected. The mean percentage cigarette reduction with the 45 mg patch was 49%, even though the levels of cotinine increased by 69%. Nevertheless, this level of reduction was greater than that seen during an inpatient study in which smokers received doses ranging from placebo to 63 mg (3, 21 mg, 24-hour patches) for a period of 5 days. Benowitz et al., (1998)
saw a maximum of a 26% reduction in cigarettes at the highest dose as compared to placebo patch. This modest reduction was observed in the face of a 250% increase in plasma nicotine levels. The lower level of reduction observed in their study was attributed to the study’s inpatient setting, with its limited exposure to smoking cues that typically occur in the subject’s natural environment, leading to lower rates of smoking across all conditions including placebo. In fact, the authors noted that overall smoking on the unit was diminished, with pre-clinic ad libitum smoking of 29 cigarettes/day compared to just 17 cigarettes/day while the smokers were on placebo patch on the unit. Similar observations were made in another inpatient study in which smokers were assigned to 0, 22 and 44 mg 24-hour patches in randomized, counterbalanced order, with each patch dose worn for a period of 1 week (Pickworth et al., 1994). In the higher dose condition, subjects attained a 215% increase in nicotine concentration and only a 21% decrease in cigarettes compared to the placebo condition. Thus, very high doses of nicotine delivered transdermally do not lead to dramatic reductions in cigarettes smoked, particularly among smokers not interested in quitting or, as in the case of the two inpatient studies, in reducing.
This study also showed that absolute reductions in both carbon monoxide and total NNAL were not proportional to reductions in cigarettes/day, as has been observed in previous studies (e.g., Fagerstrom & Hughes, 2002
;Hecht, Murphy et al., 2004
;Hughes & Carpenter, 2005
). In a review conducted by Hughes and Carpenter (2005)
, studies on cigarette reduction interventions for smokers not trying to quit were examined. Of the studies that used typical doses of NRT and that described both reductions in cigarettes per day and CO, the respective mean reductions were 39% (range = 18%-66%) and 27% (range= 10% to 46%). In the review by Fagerstrom and Hughes (2002)
, studies using usual doses of gum, inhaler or patches with instructions or intentions to reduce, the mean reduction in cigarettes was about 50% and the mean reduction in CO was about 30%. In nicotine patch studies that involved instructions to smoke cigarettes ad libitum, the mean cigarette reduction was about 40% and the mean CO reduction was about 30%. We observed similar reductions in cigarettes (49%) and CO (37%) with the 45 mg patch. With carbon monoxide’s short half-life, reductions should have been immediately apparent at any of the doses; on the other hand, the time of last cigarette may have a significant influence on this biomarker of exposure. Total NNAL is a better biomarker of exposure because of its longer half-life, however, the modest changes in levels of total NNAL (24%) relative to the changes observed for CO (37%) must be interpreted cautiously because of its elimination half-life of approximately 40 – 45 days (Hecht et al., 1999
). Therefore, lower total NNAL levels may be observed with longer duration on the patch. It is unknown whether or not the reductions in carbon monoxide and total NNAL observed in this study would reduce disease risk, however even these modest reductions may have a significant population impact.
Apart from the question of absolute reductions in smoking and biomarkers of exposure is the issue of compensatory smoking for nicotine and relative exposure to toxicants, such as CO and NNAL, on a per cigarette basis. Benowitz et al. (1998)
reported that the average nicotine intake from cigarette smoking was observed to be reduced by 40% on the highest dose patch (i.e., 63 mg). This finding suggests that there was a general decreased inhalation of mainstream smoke. Furthermore, based on our calculations of the data presented in the Benowitz paper, the ER for area under the curve blood carboxyhemoglobin was 0.976 at the 63 mg patch, which would indicate no compensation. Although nicotine levels were not measured in our study, we did measure tobacco toxicants associated with tobacco intake. Unlike the results from the Benowitz et al., (1998)
study, we observed that ER for CO and NNAL both increased substantially. CO exposure per cigarette increased by a factor of 1.66 and total NNAL increased by a factor of 2.45. The reason for the discrepancy in results between these two studies is unknown except perhaps again the differences in the settings of each of these studies – an inpatient where there are few cues that are normally associated with smoking versus outpatient in which smokers are in their natural environment.
We found a relationship between the amount of cigarette reduction and the extent of exposure per cigarette, such that, the greater the reduction in smoking, the greater the extent of exposure per cigarette, even with increasing levels of cotinine resulting from the assignment to higher doses of transdermal nicotine. Several reasons may account for this counterintuitive finding. Higher doses of nicotine may result in greater desensitization of brain nicotinic cholinergic receptors and therefore less reinforcement from nicotine (Benowitz et al., 1998
). This blunted reinforcement or tolerance may lead to greater inhalation per cigarette. Alternatively, nicotine replacement that is delivered transdermally may not result in smoke exposure reduction that may be observed if nicotine was administered in a bolus fashion as found with cigarettes. The smoker may be compensating for the lack of rapid delivery of nicotine to the brain. Perhaps a combination of high dose nicotine plus an ad libitum NRT, such as nicotine nasal spray, may have resulted in greater reductions in cigarettes and less smoke exposure per cigarette. It is also possible that with decreasing cigarettes, smokers are compensating for constituents other than nicotine (e.g., MAO inhibitors, Fowler et al., 2003
) or for the sensory stimulation from smoking (Rose, 2006
;Rose et al., 1993
As a final point, the mean reduction of cigarette smoking and the mean exposure ratio do not reveal the individual variability that is associated with the response to the nicotine patch. For example, a significant number of smokers showed a greater than 50% reduction in smoking. Future studies, the reasons associated with these differences (e.g., nicotine metabolism, extent of desensitization of receptors) should be investigated.
Four main limitations are associated with this study. First, we were not able to verify the number of cigarettes smoked and it is possible that subjects underreported their cigarette intake. However, there was no reason for inaccurate reporting because no smoking reduction level was required of the subjects. Second, we were not able to objectively verify the actual amount of nicotine patch use. Subjects were asked to return all used and unused patches; however, due to lost and inadvertently discarded patches, a full, objective accounting of patch use was not possible. Third, because this was a pilot study primarily designed to examine safety, we failed to use a placebo patch which would be critical in examining the actual impact of NRT on smoking behavior. Furthermore, the safety context of this study and the concern over the administration of three nicotine patches may have significantly impacted smoking rate. Finally, the blood concentrations during the assessment period for the 45 mg patch may not have been optimal because the third patch was applied at noon rather than in the morning and patches were removed during the evening to minimize potential side effects. This method of patch administration may not have led to the greatest impact on smoking behavior.
In summary, the results of this study showed that high doses of nicotine replacement are safe when used on an outpatient basis in dependent smokers. It also led to reductions in smoking and biomarkers of exposure in a sample of smokers who were interested but not required to reduce their cigarette consumption. Nonetheless, even with the attainment of high nicotine replacement levels as reflected by the increase in cotinine, a significant number of subjects appear to have increased inhalation of mainstream smoke per cigarette, as reflected by relative increases of two tobacco toxicants, CO and NNAL, per cigarette. This finding would suggest that the use of high doses of transdermal nicotine can reduce exposure to toxicants but to levels that may or may not lead to reduced health risk due to compensatory smoking.