A randomised trial of glucose tablets to aid smoking cessation

Transcription

1 DOI /s ORIGINAL INVESTIGATION A randomised trial of glucose tablets to aid smoking cessation Robert West & Sylvia May & Andy McEwen & Hayden McRobbie & Peter Hajek & Eleni Vangeli Received: 11 June 2009 / Accepted: 28 September 2009 # Springer-Verlag 2009 Abstract Rationale Oral glucose has been found to decrease tobacco craving among abstaining smokers. One study has demonstrated an effect of glucose on short-term abstinence. There is a need to examine any long-term benefit of glucose on abstinence. Objectives To assess whether glucose tablets improve 6-month continuous abstinence rates compared with lowcalorie placebo tablets. Methods Smokers attempting to stop(n=928) were randomised to receive glucose or sorbitol (placebo) in a doubleblind placebo-controlled trial. All participants received group-based psychological support, and approximately half (n=474) received nicotine replacement therapy (NRT), buproprion, or both. Smokers were seen weekly for 5 weeks and used tablets ad libitum, with a recommended minimum of 12 per day. Participants were recruited through general practitioner referral, word of mouth, and advertising. The R. West (*) Cancer Research UK Health Behaviour Research Centre, Department of Epidemiology and Public Health, University College London, London WC1E 6BT, UK robert.west@ucl.ac.uk S. May : A. McEwen : E. Vangeli Health Behaviour Research Centre, University College London, London, UK H. McRobbie Clinical Trials Research Unit, University of Auckland, Auckland, New Zealand P. Hajek Wolfson Institute of Preventive Medicine, Barts and the London, Queen Mary s School of Medicine and Dentistry, London, UK participants were 38% male, smoked an average of 23.5 cigarettes per day, and had a mean age of 44 years. There were no significant pretreatment differences between groups. The primary outcome measure was continuous, CO-verified abstinence from the target quit date for 6 months. Results No significant effect of glucose tablets on abstinence was found (14.6% vs 13.4% abstinence in the glucose and placebo groups, respectively). However, there was a significant interaction with a glucose effect observed in smokers also receiving other medication (18.2% vs 12.6%, p<0.05) but not otherwise (10.7% vs 14.3%; p< 0.05 for the interaction). Conclusions No significant effect of glucose tablets over and above sweet tasting tablets could be detected overall, but the possibility of an effect as an adjunct to NRT or bupropion merits further investigation. Keywords Glucose. Smoking cessation. Tobacco. Abstinence. RCT Smoking cessation increases life expectancy and improves quality of life (Doll et al. 1994). It is widely recognised that it is difficult to achieve, and when studied prospectively, fewer than 5% of unaided quit attempts result in abstinence for 6 months or more (Hughes et al. 2004).The heart of the problem lies in nicotine dependence which can be regarded as a disorder of motivation resulting from repeated ingestion of nicotine. Psychological support improves chances of long-term abstinence following a quit attempt by some 5 percentage points (Lancaster and Stead 2000). Nicotine replacement therapy (NRT), bupropion (zyban), and varenicline (champix) increase long-term abstinence rates by 5 to 14 percentage points depending on the context (Cahill et al. 2008; Hughes et al. 2007; Stead et al. 2008). For many parts of the world, and many smokers, these

2 treatments are either unavailable or too expensive. The possibility that there might be a very low cost treatment that would have minimal adverse effects is one that is very attractive. In addition, it may be that combining treatments could yield higher success rates. Combining medications potentially poses issues of drug interactions and also increases cost. Adding a very low cost treatment that is unlikely to interact adversely with other medications is worth investigating. This paper reports results from a randomised controlled trial of an inexpensive intervention, glucose tablets, which may be considered either as an alternative to, or an adjunct to, existing treatments. The rationale behind use of glucose tablets is as follows: Nicotine acutely reduces appetite (Perkins et al. 1991), and abstinence from smoking leads to an increase in appetite (Hughes 1992). There is some evidence that this increase particularly focuses on carbohydrates (Helmers and Young 1998). Smokers also report strong cravings for cigarettes when they abstain (West and Schneider 1987); the strength of these cravings seems to be disproportionate to the relatively modest hedonic effects that nicotine produces; the cravings are comparable with those reported for drugs with much more powerful euphoriant actions (Hughes et al. 1994). It is hypothesised that these cravings, at least in part, arise from sensations that would in other circumstances be labelled as hunger but which come to be labelled as craving because smoking a cigarette relieves them. If this is the case, one would expect that an intervention that could rapidly mitigate what might be termed physiological hunger would reduce sensations associated with these and hence, craving. One obvious intervention is glucose tablets. Chewing these tablets produces a rapid rise in blood glucose levels, and the glucose also probably activates receptors in the mouth and stomach which increase satiety. Therefore, one would expect chewing glucose tablets to reduce cigarette craving. This hypothesis has been tested in a number of experimental studies. In one study, smokers attending a smokers' clinic who had been abstinent for 1 week were randomly assigned to chew either glucose tablets or a lowcalorie sweet for the following week. Those who chewed glucose gave lower ratings of urges to smoke than those on the low-calorie sweets (McRobbie and Hajek 2004). In another study, smokers not wishing to stop smoking for good but who usually smoked within 30 min of waking chewed either glucose tablets or placebos matched as far as possible for taste and texture following a period of approximately 12 h of abstinence (West et al. 1999). Reported urges to smoke decreased more in the glucose tablet condition compared with the control tablet condition, with an effect seen after 10 min (West et al. 1999). Not all studies have found this effect, however. Jarvik et al. (1998) failed to find an effect of glucose on cravings but the effective sample size of abstinent subjects was very small (N=5). Harakas and Foulds (2002) failed to find a significant effect of glucose tablets using a design very similar to that reported by West et al. and the same tablet formulation. There was a small reduction in strength of desire to smoke but it was not significantly larger than in the placebo group. One possible explanation is that they used a less dependent population of younger smokers, and indeed, the baseline ratings of urges to smoke were substantially lower than those in the study of West et al. McRobbie and Hajek (2004) also found a significant effect of glucose tablets on withdrawal discomfort in smokers attending a smokers' clinic and using bupropion, but not specifically on craving. An earlier study by Helmers and Young (1998) had found that sucrose reduced withdrawal discomfort but could not test for an effect on craving because of chance differences in this measure at baseline. More recently, Berlin et al. (2005) found that a glucose drink significantly reduced craving for cigarettes in abstaining smokers compared with a sweet tasting control, and that this was mediated by an increase in tryptophan uptake into the central nervous system. Tryptophan is a serotonin precursor, and this would be expected to raise brain serotonin levels in a manner that might reduce physiological hunger (West 2001). If glucose reduces craving, it might also improve abstinence rates. Severity of craving for cigarettes has been found in a number of studies to predict relapse back to smoking (e.g. Doherty et al. 1995; Killen and Fortmann 1997), and there is an obvious logical connection between the two. Only one adequately powered study has been published on the effects of glucose tablets on abstinence, and this found that glucose increased 4-week abstinence rates above placebo tablets, and that the effect was similar in those using and not using nicotine patches (West and Willis 1998). The present study aimed to assess whether chewing glucose tablets would improve 6-month continuous abstinence rates compared with low-calorie placebo tablets in smokers attending a smokers' clinic. This would provide further evidence on the potential utility of this treatment as a smoking cessation aid. Approximately, half of the participants in the study used nicotine replacement therapy or bupropion, and so, it was possible to examine whether glucose would be useful as an adjunctive treatment. Methods Design and study sample This was a double-blind placebo-controlled randomised trial with two main groups: (1) glucose tablets plus group-

3 based psychological support (GPS) and (2) placebo tablets plus GPS. Ethics committee approval was obtained, and participants who gave written informed consent to take part in the trial were individually randomised to one of the two conditions by computer-generated random numbers. In addition, at approximately the half-way point in the study, NRT and bupropion were made available as reimbursable medicines in the UK, and from that point onwards, all participants were offered these medications. A total of 928 smokers were entered into the study; 452 were assigned to the glucose group and 476 to the placebo. A total of 452 participants received no additional medication, 255 received NRT, 188 received bupropion, and 31 received a combination of both. There were no significant differences between glucose and placebo groups with regard to use of additional medication. Table 1 shows details of the participants in each group. There were no significant differences between the characteristics of the groups. The primary outcome measure was continuous lapsefree abstinence from cigarettes for 6 months; this was operationalised as attendance at all postabstinence sessions (weeks1, 2, 3, 4, and 26), self-reported lapse-free abstinence from the quit date at each of those sessions, and expired air carbon monoxide concentration of less than 10 ppm at each session. In accordance with the conventional practice for smoking cessation trials, participants lost to follow-up were considered to have relapsed (West et al. 2005). The effect of the intervention was ascertained by means of logistic regression with glucose group, accompanying medication and the interaction between glucose and accompanying medication entered together as predictor variables. This would detect any effect of glucose, of the accompanying medication, and whether glucose was more or less effective when accompanied by other medication. It was decided that all accompanying medication would be grouped together because to treat NRT and bupropion separately would have resulted in minimal power to detect an effect. The study sample was chosen to give a greater than 80% chance of detecting an increase of 7 percentage points over a placebo quit rate of 10%. This is the size of effect that would be expected given the West and Willis study and is similar to the effect found with nicotine replacement therapy. Materials and instructions Producing palatable chewable tablets that have a consistency and flavour similar to glucose tablets presents considerable challenges. The manufacturer that had supplied the mixture for the placebo tablets in the earlier studies was not willing to provide materials for this study. After testing a variety of placebo mixtures made to our specification, none of which were sufficiently palatable, and it was decided to use commercially available lemon flavoured Vivil tablets as the placebo. These contain sorbitol as a sweetener; they are round and readily chewed. They are marketed as sweets for diabetics. This then dictated the composition, size, shape, and flavouring of the glucose tablets which were manufactured to order. The tablets were made from glucose with magnesium stearate for binding and a small amount of lemon flavouring to match the placebos. Each tablet contained 3 g of glucose. Participants were instructed to chew the tablets when they felt an urge to smoke but to try to ensure that they chewed a minimum of 12 per day. They were given one box of 105 tablets to last them for the following week, but if they considered that they would need more, they were given two boxes. Participants could contact the clinic to request additional supplies if they needed them before the next scheduled session. At the end of the final session, 4 weeks after the quit date, they were given enough tablets to last them for a further 2 weeks if they wished. Table 1 Characteristics of the study sample Glucose group Placebo group Total Mean (SD) age (years) 44.5 (12.67) 44.4 (12.29) 44.4 (12.47) Percent male Percent in manual occupational group Mean (SD) daily cigarette consumption 23.0 (9.01) 24.0 (9.04) 23.5 (9.04) Mean (SD) baseline expired air CO (ppm) 25.8 (10.87) 26.7 (11.09) 26.3 (10.99) Mean (SD) FTND 5.7 (2.25) 5.9 (2.29) 5.8 (2.28) Percent who had stopped smoking in the past Mean (SD) duration of longest previous period of abstinence (weeks) 32.7 (89.28) 27.4 (78.32) 29.9 (83.85) Percent who had used NRT in the past SD standard deviation

4 Procedure Smokers were recruited through advertisements in local papers, word of mouth, and general practitioner referrals. Participants were assessed for eligibility by phone, and smokers who were under 18, diabetic, currently smoking less than 10 cigarettes a day, unable to read and write English, or who responded affirmatively to a question that asked whether they had a current psychiatric condition were excluded. Participants were then invited to the next available group. Information on demographic characteristics and smoking patterns, including the Fagerstrom Test for Nicotine Dependence (FTND) were gathered by means of a postal questionnaire prior to session one. Participants were seen in groups of about 30 smokers. Smokers attended an initial session 1 week before the quit date and then reattended on the quit date and weekly for 4 weeks afterwards (a total of six visits). They were also followed up 26 weeks after the quit date. All the participants in a group stopped smoking on the same day (visit 2), were randomised, and began using their tablets at that point. Therefore, only those who attended visit 2 are included in the analyses. There were no significant differences between those who did and did not attend visit 2. Sessions took about 60 minandmainlyconsisted of group-based discussions. However, at the start of each session, participants were briefly seen individually, CO readings taken, and tablets dispensed. If a participant did not attend an appointment, an attempt was made to contact them and arrange a new appointment as soon as possible. If a person could not be contacted or did not attend the new appointment within 3 days, they were assumed to have resumed smoking. Six months after their quit date (plus or minus 7 days), participants who were continuously abstinent at the end of treatment were contacted again and invited to attend a follow-up appointment where their CO reading was taken. Those who claimed no smoking at all during the quit date and had expired air CO concentrations less than 10 ppm were considered as successes, while all other smokers were considered to have smoked. Results Compliance with the tablet regimen was generally good initially but reduced over time. The mean daily consumption was 15.1, 11.4, 10.1, and 8.8 in weeks1 to 4, respectively. There was no difference between the active and placebo groups. A total of 245 out of 452 eligible participants failed to attend at least one session in the glucose group, and 254 out of 476 eligible participants failed to attend at least one session in the placebo group. (Participants were eligible for follow up if they had attended all previous sessions and were confirmed as abstinent by expired air CO). There was no difference between the groups in follow-up rates. All those not attending one or more sessions were counted as smokers. Table 2 shows the abstinence rates in the four conditions. There was no overall effect of the glucose tablets on abstinence (14.6% vs 13.4% p=not significant). However, there was a significant interaction between the glucose and medication conditions at 6 months. Looking at the medication and no medication conditions separately, it was apparent that the interaction was due to greater abstinence in the glucose condition but only in the presence of medication. In the nonmedication condition, the abstinence rate for the glucose subjects was nonsignificantly lower than for the placebo group. We undertook a number of secondary analyses to determine whether the effect of glucose was influenced by dependence, gender, and numbers of tablets consumed, but no evidence for this was found. Discussion No clear effect of glucose tablets on abstinence could be detected although there was evidence for an interaction between glucose and use of other medication, such that continuous abstinence up to 6 months was higher in those taking glucose but only in those also taking NRT or bupropion. Table 2 Percent (N) abstinent in the four conditions Placebo glucose + no medication Active glucose + no medication Placebo glucose + medication Active glucose + medication Week (104) 43.5 (93) 62.2 (148) 65.3 (154)* Week (83) 34.1 (73) 43.7 (104) 53.0 (125)*, ** Week (76) 29.4 (63) 37.8 (90) 46.6 (110)*, ** Week (70) 28.5 (61) 37.0 (88) 45.8 (108)*, ** Week (34) 10.7 (23) 12.6 (30) 18.2 (43)**, *** *p<0.05, for medication versus no medication; **p<0.05, for the active versus placebo glucose in those receiving medication; ***p<0.05, for the interaction between glucose and medication conditions

5 The failure to find an effect of glucose alone does not lend support to the idea that this can improve abstinence rates in the long term. Our data conflict with our earlier finding that glucose tablets improved 4-week abstinence rates in smokers whether or not they were using nicotine patches (West and Willis 1998). There are a number of possible explanations for this. The results may be due to cohort or participant differences (e.g. in the earlier study the mean age was lower (41.5 years), and the average scores were higher on the dependence measures). The tablets used were different, and this may also have had an effect, for example on palatability. Interestingly, in the West and Willis study usage was higher among abstinent smokers in the glucose than the control condition. That was not the case in the current study. Usage in the current study was high for both conditions (i.e. 45 g per day) compared to only 12 g per day in the West and Willis study. Participants randomised to receive medication in the previous study used the 15-mg patch; however, in the current study, different forms and doses of medication were used. Finally, it is possible that either the earlier finding was a false positive, or that this one is a false negative. The present study had 80% power to detect an increase in 7 percentage points, and a difference of only 1.2 percentage points was observed. This study used the strictest possible criteria for determining treatment success, with no lapses allowed at any point. If glucose had an effect on preventing lapses from leading to full relapse, this study would not be able to detect it. These results suggest that if there is a long-term effect of glucose on abstinence, it is likely to be small and may be limited only to those people already using NRT or bupropion. The very low cost of glucose would make it cost-effective as an aid to cessation even if the effect size were less than 1%, but it is unlikely that any study would ever be funded to detect an effect of this size. However, the potential for glucose to improve success rates in smokers using other medications is worth further examination. If the effect of glucose in those taking smoking cessation medications is replicable, the question arises as to what underlies this. One possible explanation is that, by itself, adding glucose to the diet has only a small effect on motivation to smoke which, in the absence of other interventions that may reduce this motivation, is insufficient to cross a threshold. However, if another intervention can get a number of smokers near the effectiveness threshold, glucose may be able to push them over it. Of course, this is highly speculative, and further speculation should await replication. 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