-* My personal expertise -* The myth of nicotine addiction -* Justification of the galenic forms of nicotine -* Commercial development of nicotine -* The « Nicotine Addiction » report -* Is nicotine addictive? -* Is nicotine efficient? -* Financial issue -** Reimbursement -** Free providing -* Nicotine effects -** Glycaemia -** Stimulation -** Relaxation -* Nicotine and brain reward system -* Conclusion| Subject: Updating AFSSAPS recommendations 2003 – Guidance Note on smoking cessation: from identification to maintenance of abstinence. Fournes-en-Weppes, June 27, 2012
_ To Professor Jean-Luc HAROUSSEAU _
President of the HAS _
2 Avenue du Stade de France
_ 93218 Saint Denis la Plaine Cedex Mr President,
The hospital Paul Guiraud in Villejuif where I keep on working voluntarily, has given to me the guidance note on the update of recommendations for good practice on aid to smoking cessation, published by AFSSAPS in 2003. It seems indeed necessary that new recommendations be enacted, especially as the trend is that these recommendations will become opposable to doctors one day. It is therefore of utmost importance that they are consistent with the best scientific evidence and free from commercial influence, which was not the case with the 2003 recommendations. As a board member of Formindep and in charge of matters relating to smoking, I am instructed by the President to share with you my thoughts about these recommendations. [expertise<-]
My personal expertise
I think I have particularly good expertise on tobacco and smoking. – Clinical. I opened in 1977 at Nanterre Hospital one of the first clinic for patients who wish to stop smoking, and continues to this day at the Hospital Paul Guiraud. I personally always assured these consultations.
- Experimental. I spent my lab activity in my laboratory of Experimental Medicine in the Paris V University. My research topic was the mechanism of addiction to tobacco and its components. I keep on working in this field in the laboratory of neuro-psychopharmacology of Dr Renaud de Beaurepaire, at the Paul Guiraud hospital.
- Associative. I founded in 1983, the Société d’Etude de la Dépendance Tabagique, which became in 1990 Société de Tabacologie, according to a neologism that I proposed. I chaired it until 2004. – Teaching. I created in 1986 at Paris V the University Diploma Dépendance tabagique et phénomènes comportementaux apparentés, which I coordinated until 2009 under the name Diplôme Interuniversitaire de Tabacologie Paris XI-Paris XII. I believe this is the world first coordinated teaching about it.
- I opened the website www.tabac-humain.com to continue to disseminate this teaching, which I could no longer do within the University due to my retirement.
This expertise earned me to be automatically registered in the 2003 working group of AFSSAPS [[French agency for security of sanitary products]], chaired by Professor Gilbert Lagrue. However, I did not participate in the development of its recommendations. Indeed, the decree implementing Article 26 of the 2002 March 4 Law (Decree 2007-454 of 2007 March 25) not having been published then, the various experts involved in the drafting of these recommendations were not required to report their links of interest. It seemed clear, however, that this group was under the dominant influence of GSK and Pfizer, Pierre Fabre Santé and Novartis. Having had the experience of meetings in the AFSSAPS and in two at INPES [[National institute for health prevention]] in a similar context, I fully understood that my arguments had no chance to be heard. Thus, the vast literature of the studies analyzed was not submitted to the necessary objective criticism, while the studies cited are mostly funded by the pharmaceutical industry [[Etter JF, Burri M, Stapleton J. The impact of pharmaceutical company funding on results of randomized trials of nicotine replacement therapy for smoking cessation: a meta-analysis. Addiction (2007) 102 (5): 815-22. Etter JF, Stapleton J Citations to trials of nicotine replacement therapy were biased toward positive results and high-impact-factor journals. J. Clin. Epidemiol. (2009) 62 (8): 831-7.]]
Thus these recommendations seem more like an official support to the promotion of medication, which at the time was essentially nicotine, « NRT ». But the Guidance Note expressly refers to the update of the 2000 U.S. Guideline. [[U.S. Department of Health and Human Services. Treating tobacco use and dependence: 2008 update. Clinical practice guideline. Washington: Public Health Services, (2008). Ref ID: 68]], and reflects its spirit. Given the considerable links of interest of US opinion leaders with pharmaceutical companies manufacturing or selling smoking cessation drugs, I have the deepest concerns about the independence of the future recommendations. Back to top
[myth<-]The myth of nicotine addiction
Ove Ferno, a Swedish chemist at the firm LEO, told in an interview the saga of the development of nicotine gum, from 1967 to the patent in 1978 [[Conversation with Ove Ferno. Addiction (1994) 89, 10: 1215-1226]]. Based on self-observation, he was convinced that nicotine was the factor of tobacco dependence. Yet the team of Russell in London was already questioning the theory [[Kumar R, Cooke EC, Lader MH, Russell MAH. Is nicotine important in tobacco smoking? Clin Pharmacol Ther (1977) 21: 520-529]]. In fact, simple observations could suffice to question that nicotine alone explains the powerful tobacco dependence: – Usually, when a chemist isolates an active molecule from an addictive plant, drug addicts get hold of it quickly (morphine from opium, cocaine from coca leaves, tetrahydrocannabinol from cannabis, etc).
- We have known nicotine for a century and a half. It has been extracted, synthesized, used as an insecticide, yet we have no observation of its use for addictive purposes.
- During wars, when tobacco was rare and its availability limited, we had no reports of addition of nicotine to various dried leaves, wormwood, walnut and so on used as tobacco substitutes.
- Under the same conditions, no smuggling or any kind of traffic of nicotine has ever been reported.
- The pure nicotine can be obtained from chemical companies (Fluka) at a price of €440 per liter, which for 1 euro would make up 143 packs of 20 cigarettes. No « drug » is available at such a low price. Back to top [justification<-]
Justification of the galenic forms of nicotine
Nicotine is a natural product, described a long time ago, as was its methods of extraction or synthesis. Nothing relating to nicotine is patentable anymore. Its price is extremely low for a toxic dose. Pharmaceutical companies wishing to commercialize it were thus faced with a problem of profitability. Simple formulations for nicotine ingestion, such as tablets or solutions, were inexpensive, unprotected by patents, thus exposed to competition. It was absolutely necessary to increase the « price regulation ». The answer came from the exploitation of the effect of liver first-pass. The argument is that ingested nicotine is absorbed through the gut. The portal circulation would bring it to the liver, where it would be destroyed before reaching the systemic circulation. It would therefore be ineffective. Thus it was necessary to imagine routes of administration bypassing the liver. As oral, nasal mucous membranes and skin are drained by peripheral veins, nicotine by these routes reaches directly the right heart, from which it gets to the brain, after passing the pulmonary circuit (which an inhaler can bypass). Thus patentable and high margins gums, patches, inhalers, nasal sprays were developed. A major objection is that the destruction of ingested nicotine by the liver is not complete. It has long been known that a third of the ingested dose escapes and goes directly to the systemic circulation [[Benowitz NL, Jacob P III, C. Savanapridi Determinants of nicotine intake while chewing nicotine gum polyacrilex. Clin. Pharmacol. Therap. (1987) 41: 467-73]]. At body pH, a third of the nicotine is not ionized and is very liposoluble. It may follow the absorption of fat chilomicrons through the thoracic duct to the Pirogoff confluent, thus bypass the liver. Thus the ingestion of 4 mg of nicotine in a glass of water would bring 30% of it in the arterial blood, ie 1.2 mg, exactly the amount provided by a 4 mg gum. It has been pointed out that it takes 7 to 9 seconds only for the nicotine inhaled from a puff to get to the brain. A peak of blood nicotine would be renewed every breath, creating repeated cerebral « shots » of nicotine. These peaks are considered critical to the establishment and maintenance of addiction, and explain the success of cigarette. However, positron tomography showed that these peaks do not exist in the brain. Labelled nicotine accumulates very gradually to reach a maximum in about 5 minutes [[Rose JE, Mukhin AG, Lokitz SJ, Turkington TJ, Herskovic J, Behmb FM, Gargc S, Gargc PK. Kinetics of brain nicotine accumulation in dependent and non-dependent smokers assessed with PET and cigarettes containing 11C-nicotine. PNAS, (2010),107, 5190-5]]. More simply, the tobacco chewers or snuffers are extremely dependent, without such peaks. Back to top [Commercial<-]
Commercial development of nicotine
Karl Fagerström, a graduate of psychology in 1975, worked then on his thesis with LEO gum. In 1978, he created a test to evaluate the dependence of smokers, the FTQ (Fagerström Tolerance Questionnaire). The title is neutral and quite incomprehensible, but Fagerström expressed also clearly that the aim was to measure nicotine dependence, which was regarded to explain tobacco dependence [[Fagerstrom KO, Schneider NG. Measuring nicotine dependence: a review of the Fagerstrom Tolerance Questionnaire. J. Behav. Med (1989) Apr; 12 (2): 159-82]]. In 1983, he joined the firm, that had become Pharmacia & Upjohn, where he is Director of scientific information on nicotine replacement therapy. [report<-]
The « Nicotine Addiction » report [[The health consequences of smoking. Nicotine Addiction. A report of the Surgeon General (1988). 1 vol. 639p]]
This report, which provides the basis of the entire development of the « nicotine replacement therapy », is based on a syllogism:
- Premise 1: Tobacco causes a powerful addiction; – Premise 2: Tobacco contains nicotine, a poison neurotropic rare in other plants; – Conclusion: Nicotine is responsible for tobacco dependence. But this is in fact pure sophistry. Tobacco contains so many other substances, which may act in synergy, possibly with nicotine, that we can not draw such a conclusion. Moreover, in this huge book with 3,200 references, we would look in vain for a single article showing that Man can be dependent on nicotine only. On the other hand, the « Treatment » chapter focuses immediately on the « Nicotine replacement therapy ». But then we did not have any hindsight about the efficiency of this new treatment, because the FDA had just approved the marketing of the 2 mg gum. But the case was launched. The « Test of Nicotine Dependence » developed by Karl Fagerström was universally distributed, including in the 2003 AFSSAPS recommendations. [[Fagerström KO, Schneider NG. Measuring nicotine dependence: a review of the Fagerstrom Tolerance Questionnaire. J. Behav. Med (1989) Apr; 12 (2): 159-82]]. He contributed to implant the idea that tobacco dependence was caused by nicotine. This justified treating with a drug that, while satisfying the need of the smoker, had none of the dangers of smoking. Yet it is a manifest semantic abuse, because none of the six items of the Fagerström’s test refers to nicotine. One in the first 8 items test, later withdrawn as irrelevant, referred to the nicotine yield of cigarettes. A factorial analysis showed quickly that most of the variance was explained by two orthogonal factors: 1 – the precocity of the first cigarette of the day and 2 – the number of cigarettes smoked daily [[Heatherton TF, Kozlowsi LT, Frecker RC, Rickert W, Robinson J. Measuring the Heaviness of Smoking: Using Self-Reported Time to First Cigarette of the Day and Number of Cigarettes Smoked per Day British Journal of Addiction, (1989) 84: 791-799]]. So this test is a test of cigarette addiction only. This was finally recognized by Fagerström himself, breaking off from his sponsors, after having for years poisoned minds, asking that the title of his test be changed. [[Fagerström KO. Determinants of Tobacco Use and Renaming the FTND to the Fagerström Test for Cigarette Dependence. Nicotine & Tobacco Research+ Advance Access published October 24, 2011]]. Back to top [addictive<-]
Is nicotine addictive?
It is the key question. We can already note that there is no example of any initial use of nicotine alone as a « drug », while addicts are quick to adopt the purified molecules extracted from plants on which they are dependent. The only possibility is the persistence of a residual addiction to nicotine alone, induced in ex-smokers by their prior use of tobacco.
- Although it has long been available as an insecticide, we have no example of using nicotine as a substitute during periods of tobacco shortage.
- In early studies on nicotine gum against a placebo, the percentage of subjects who stopped smoking but continue to chew the gum after a year is virtually identical, whether they were taking active gum or gum placebo, ie 44% and 42% [[Jarvis MJ, Raw M, Russell MA, Feyerabend C. Randomised controlled trial of nicotine chewing-gum. BMJ (Clin Res Ed) (1982) 285 (6341): 537-40.]]. Two factors may be invoked to explain such a high percentage in both groups: 1. – A chewing habit. 2. – The fear of lighting a cigarette if they stop chewing the gum. – The long-term use of nicotine replacement among former smokers previously very addicted is pretty rare and questionable. After a year, only 6% were still using the gum. [[Shiffman S, Hughes J R, Di Marino ME, Sweeney CT. Patterns of over-the-counter nicotine gum use: persistent use and concurrent smoking. Addiction (2003) 98, 1747-53]]. A 2007 study confirms the low level of prolonged use. Out of 1,518 patients, 76 (5%) only continued to use nicotine after one year, whose 2% as patches, 7% sublingual tablets, 8% lozenges, 8% inhalers, 9% gums, and 13% nasal sprays [[Hajek P, McRobbie H, Gillison F. Dependence potential of nicotine replacement treatments: Effects of product type, patient characteristics, and cost to user. Preventive Medicine (2007) 44: 230–4]]. Very addicted tobacco smokers do not show a strong addiction to nicotine, as evidenced by the very small percentage of longtime users of patches. When sensory stimulation is associated, this percentage increases, but remains well below what would have been expected from the substitution of an addictive plant by its purified active molecule. Instead, the active molecule is much more addictive in general than the original plant, and even often supplants its use. The « Nicotine titration » phenomenon is a strong argument in favor of research by the smoker of a satisfactory optimal dose of nicotine. Thus, if we change his cigarettes, he modifies his smoking parameters to keep constant his nicotine dose [[Russell MAH, Sutton SR, Feyerabend C, Saloojee Y. Smokers response to shortened cigarettes. Dose reduction without dilution of tobacco smoke. Clin. Pharm. Therap. (1980) 27 (2): 210-8]]. Smokers are able to extract the same amount of nicotine from low and high yield cigarettes [[Benowitz NL, Hall SM, Herning RI, Jacob P III, Jones RT, Osman AL: Smokers of low yield cigarettes do not consume less nicotine. New Eng. J. Med. (1983), 139-42]]. In my laboratory, Caroline Cohen showed that when smoking at the same pace in 30 minutes two different cigarettes yielding equal CO and tar, the high-yield cigarettes were smoked less completely than regular cigarettes, and that smokers spontaneously lighted their own cigarettes later and smoked them less completely. They did not like at all these high-yield cigarettes, which they felt frankly aversive. Thus nicotine has a satiating, but not a rewarding effect, [[Cohen C: Facteurs pharmacologiques de la dépendance à l’égard du tabac. Thèse Doctorat Sciences. PARIS XI-ORSAY. (1989); 214p.]]. Also, in all my tests on rats, nicotine has been shown regularly aversive. We can therefore hypothesize that the titration phenomenon, rather than expressing the research of a reward minimal dose (threshold effect), rather express a « ceiling effect », limiting consumption before the dose becomes aversive. In the event that the smoker could adjust his absorption of nicotine at a personal best, it was logical to try to improve the success of nicotine replacement therapy by adapting the dose to that absorbed by the smoker spontaneously, calculated from the salivary cotinine. The result is absolutely negative. [[Berlin I, Jacob N, Coudert M, Perriot J, Schultz L, Rodon N. Adjustment of Nicotine Replacement Therapies According to Saliva Cotinine Concentration: the ADONIS trial: A Randomised Study in Smokers with Medical Comorbidities. Addiction. (2011) 106(4): 833-43]]. Back to top [efficient<-]
Is nicotine efficient?
A large majority of publications agree that nicotine gum improves the success of quit attempts. However, the percentage of abstainers remains at a low level. Thus, a meta-analysis of 14 randomized trials found that, in specialized consultations, the success of nicotine gum and placebo were respectively 27% vs 18% at 6 months and 23% vs 13% at 12 months. However, this success rate is much less bright in general practice 17% vs 13% at 6 months, and 9% vs 5% at 12 months [[Lam W, Sze PC, Sacks HS, Chalmers TC. Meta-analysis of randomised controlled trials of nicotine chewing-gum. Lancet. (1987) 2(8549):27-30]]. Regarding patches, a meta-analysis of 17 studies (N = 5098) is quite favorable, 27% vs 13% at the end of treatment, 22% vs 9% at 6 months. [[Fiore MC, Smith SS, Jorenby DE, Baker TB. The effectiveness of the nicotine patch for smoking cessation. A meta-analysis. JAMA. (1994) 271(24):1940-7.]] A very large meta-analysis by the Cochrane group in 2008 gives results that also support the same order of magnitude. It covered 40,000 smokers in 132 studies, followed during at least 6 months. For all RR = 1.58 (1.50 to 1.66), ie 1.43 for gum, 1.66 for patch, 1.90 for inhaler, 2.00 for tablets and 2.02 for the nasal spray. [[Stead LF, Perera R, BullenC,Mant D, Lancaster T. Nicotine replacement therapy for smoking cessation. Cochrane Database of Systematic Reviews (2008). Issue 1]]. However, another meta-analysis of 7 studies found results much less bright. Four dealt with gum, two with inhaler and one left free choice. The 2,767 smokers were treated for 6 to 18 months, followed for 12 to 26 months. Only 6.75% were abstinent at 6 months, as opposed to half for those on placebo [[Moore D, Aveyard P, Connock M, Wang D, Fry-Smith A, Barton P: Efficiency and safety of nicotine replacement therapy assisted reduction to stop smoking: systematic review and meta-analysis BMJ (2009) 338:b1024]]. However, some major objections temper these results of randomized double-blind trials. Although supportive, they remain modest however, averaging 1.6 times the placebo effect:
1. – In theory, if the double-blind was strict, smokers should not be able to guess what product they received in more than 50% of cases. So just ask them. They know from smoking the effects of nicotine, and are often able to guess right. In fact, the quality of the double-blind is not verified usually [[Mooney M, White T, Hatsukami D The blind spot in the nicotine replacement therapy literature: Assessment of the double-blind in clinical trials Addictive Behaviors (2004) 29 : 673–684]]. 2. – Compared with independent studies, the results of trials funded by industry are more often significant, with greater odds ratios [[Etter JF, Burri M, Stapleton J. The impact of pharmaceutical company funding on results of randomized trials of nicotine replacement therapy for smoking cessation: a meta-analysis. Addiction (2007) 102(5): 815-22]]. More, the results tend to be published in journals with broader impact [[Etter JF, Stapleton J : Citations to trials of nicotine replacement therapy were biased toward positive results and high-impact-factor journals. J Clin Epidemiol (2009)62(8): 831-7]]. 3. – Publication bias is difficult to calculate, as the trials are not systematically reported. Thus, I personally coordinated a multinational study on a nicotine patch. It was remarkably performed by a company specializing in clinical trials (Besselaar). As the results were not favorable, the company that had financed the study did not publish it. Moreover, since the « NRT » ceased to be delivered on prescription only and were freely sold « over the counter » without any psychological support, their efficiency is no longer detectable after 3 months [[Pierce JP, Gilpin EA : Impact of over-the-counter sales on effectiveness of pharmaceutical aids for smoking cessation. JAMA (2002) 288, n°10; 1260-4]]. Several meta-analysis have examined this issue. Thus, one focused on four randomized studies comparing a nicotine patch to a placebo patch, with an OR of 2.5 for nicotine. In four studies comparing prescription to over-the-counter purchase, including two randomized ones, the results are by no means homogeneous. Combined, the difference is not significant (OR = 1.4, 95% CI: 0.6 to 3.3). In the long term (beyond 6 months) abstinence rates are miserable, very inhomogeneous across studies (1% to 11%), overall 7% (95% CI: 4% to 11%). [[Hughes JR, Shiffman S, Callas P, Zhang J. A meta-analysis of the efficacy of over-the-counter nicotine replacement. Tob. Control (2003) 12(1):21-7]]. A methodological review of the literature on the interest of nicotine substitutes sold without prescription in the actual population reveals many flaws, including the provision of free substitutes, no assessment of the quality of the double-blind, lack of careful monitoring, as well as important limitations of meta-analysis. This review concluded that the superiority of over-the-counter nicotine substitutes to stop smoking without help is not convincingly demonstrated. [[Walsh RA Over-the-counter nicotine replacement therapy: a methodological review of the evidence supporting its effectiveness. Drug and Alcohol Review (2008), 27, 529 – 547]] An important aspect is the efficiency in cohort studies. In a questionnaire sent in 1998 to the participants of a cohort established in 1989, 1,954 responders were smokers in 1989. 36% had used nicotine substitutes, then available without a prescription (10% gum, 16% patch, and 10% both). Their success rate was 30%, against 39% among non-users (p <0.01) ). The authors conclude that this probably reflects a tendency of highly dependent smokers, who can not stop themselves, to use nicotine [[Alberg AJ, Patnaik JL, May JW, Hoffman SC, Gitchelle J, Comstock GW, Helzlsouer KJ: Nicotine replacement therapy use among a cohort of smokers. J Addict Dis. (2005) 24(1): 101-13]]. Another prospective study from the Harvard School of Medicine was to recruit by phone, randomly, smokers who quit in the last two years. Interviewed between January 2001 and June 2002, then in a second wave between January 2003 and June 2004, and finally between January 2005 and June 2006, their rate of abstinence was evaluated according to whether they had used nicotine substitutes and possibly advice by professionals, both or alone. The conclusion is disappointing. No effect was observed on the maintenance of abstinence, regardless of the treatment used. [[Alpert HR, Connolly GN, Biener L. A prospective cohort study challenging the effectiveness of population-based medical intervention for smoking cessation . Tob Control. (2013) 22(1): 32-7]]. Teenagers are a population in which the efficiency of a treatment is of particular importance. A meta-analysis included six randomized controlled trials involving 816 smokers aged 12 to 20 years. No significant abstinence increase was observed, nor short-term (12 weeks) nor after a 26 weeks follow-up. [[Kim Y, Myung SK, Jean YJ, Lee EH, Park CH, Seo HG, Huth BY: Effectiveness of pharmacologic therapy for smoking cessation in adolescent smokers: Meta-analysis of randomized controlled trials. Am J Health Syst Pharm (2011) 68(3): 219-26]]. Back to top [issue<-]
-*Reimbursement Initially, nicotine gums should be delivered on prescription. It was a major barrier to their diffusion, all the more so since the National health insurance did not accept reimburse them. This attitude was logical. Nicotine is not a treatment for lung cancer, myocardial or COPD. It is therefore very indirectly, uncertainly and on the long run that it could possibly prevent them. But the insurance has always refused to take responsibility for preventing, because it deals with large populations, and is therefore particularly expensive. It considers that it is the responsibility of public health policies. Unable to obtain a refund, pharmaceutical companies have lobbied for nicotine to be obtained without prescription, arguing that it was illogical to be allowed to buy it as tobacco without control or limit. Having succeeded, they were therefore allowed to advertise in the media for these products, which is prohibited for prescription drugs. But despite intense television campaigns, while no heroin addict ever needed publicity on television or on buses to discover that codeine was able to somehow relieve his withdrawal symptoms, smokers were not convinced, nicotine sales did not soar, and the overall efficiency on quitting was not increased. Lobbying then made strong pressure on the government to circumvent the prohibition against reimbursement. Drugs for smoking cessation were then presented as necessities, so that in February 2007, the government decided to grant a subsidy of €50 per year per smoker to allow the purchase of nicotine replacement therapy, reaching €150 for pregnant women. Just arrived on the market, varenicline immediately benefited from this provision, to be removed from it in June 2011 due to the increase in accidents attributed to this product. Obviously, it is health insurance that has to pay. But despite this disguised reimbursement, firms kept on to disseminate advertising, sometimes indirectly as for varenicline. « Tobacco, I stopped with my doctor! » was a Pfizer campaign launched with the partnership of various medical societies. Back to top -*[providing<-]Free providing A step closer to get support of these medications by the community is that smokers can get them for free, obviously at the expense of health insurance. Very few publications have evaluated the impact of free nicotine replacement therapy on quit success. The oldest one covers only 375 smokers. I could read the abstract only. It does not specify the distribution of groups. The employer provided the product. After a year, the success was 38% vs 27%, in favor of free nicotine. [[Cox JL, McKenna JP .Nicotine gum: does providing it free in a smoking cessation program alter success rates? J.Fam Pract (1990) Sep;31(3): 278-80]]. A large French study was conducted in the Health Insurance Centers. Two groups were formed. In the 22 centers of the group « intervention », 1,585 smokers (38% of the eligible ones) agreed to enter the study. They received a document enabling them to get from a pharmacist a free treatment for 3 months, with gum or patch as they prefer. In the 25 control centers, 2,597 smokers (45.9% of the eligible ones) received the minimum advice only. A questionnaire was sent home after 6 months to assess the evolution of smoking. 26% of questionnaires were returned in the 2 groups. 29.9% in the intervention group declared having stopped smoking vs 10.3% in the control group. [[Kuntz C, Spyckerelle Y, Giordanella JP, Baudier F. Evaluation de la prise en charge gratuite des substituts nicotiniques dans l’aide à l’arrêt du tabagisme proposée à des populations en situation de précarité dans les centres d’examens de santé. BEH (2001) 22-23: 107-9]]. This is an open study of the effect of nicotine drugs compared to a control group receiving only an advice. Successes are quite comparable to similar studies, even to some trials against placebo. This study does not analyze in any way the effect of free nicotine drugs, and can not plead in their favor. To build an experimental protocol that does not lend itself to such criticism is impossible on such an issue. However, a different approach was performed. The premise was to supply free patches for treatments ranging from 2, 4, 6 and 8 weeks to smokers motivated enough to have already called a cessation helping line. Results were judged by telephone contact after 12 months. No relationship between the dose and the success was observed. The authors acknowledge that no firm conclusions can be drawn and further studies are needed. .[[Cummings KM, Fix BV, Celestino P, Hyland A, Mahoney M, Ossip DJ, Bauer U. Does the number of free nicotine patches given to smokers calling a quitline influence quit rates: results from a quasi-experimental study Public Health (2010) 10: 181]]. Back to top [effects<-]
It seems clear that nicotine is not the only factor of tobacco dependence. But it is not an inert molecule. Some smokers can take advantage of its pharmacological effects, although it does not create any dependence, while being one of the factors capable of maintaining it. -* Glycaemia Nicotine rapidly increases blood glucose by mobilizing hepatic glycogen by adrenergic actions. By humoral way, it releases adrenaline by direct action on the adrenal medulla. By nervous way, it stimulates the post ganglionic sympathetic neuron that sends the glucosecretory nerves to the liver. Thus, the first cigarette of the day increases blood sugar more quickly than breakfast. This is confirmed by the unpublished study on a patch to which I have referred. Subjects had a biological fasting checkup in the morning before laying their first patch, and a control after 6 weeks of treatment. Blood glucose in the 76 success had not changed since the initial value, while in the 218 who had returned to their cigarettes, it had increased by 4.7% (p <0.001). This demonstrates the hyperglycaemic effect of nicotine. However, considering only the subjects who received the placebo patch, initial blood glucose in the 25 who succeeded was 5 mOs/L, while that of the 101 failures was lower, at 4.6 mOs/L. Everything happens as if some slightly hypoglycemic smokers had not supported the deprivation of their cigarettes. Hence they endure food craving. Eating is then the only way to cope with it, with body weight gain as a consequence, which in turn pushes to light a cigarette. [[Molimard R : Glucose et dépendance tabagique. Alcoologie (1996) 18 : 171-4]]. This may explain some therapeutic success of nicotine, generally limited to the first weeks of abstinence, before smokers equilibrate again their glycaemia by having a cigarette. Back to top -*[Stimulation<-]Stimulation Many smokers say that smoking stimulates them, keeps them awake, helps them working, physically and intellectually. This is clearly a stimulant action of nicotine on the locus coeruleus [[Svenson TH, Engberg C . Effect of nicotine on single cell activity in the noradrenergic nucleus locus coeruleus. Acta physiol Scand Suppl (1980);479:31-4]]. As they stop smoking, some smokers may experience a decrease in efficiency, and find an improvement by the pharmaceutical nicotine. Besides, glucose tablets have a favorable effect on the desire to smoke [[West R, Courts S, Beharry S, May S, Hajek P. Acute effect of glucose tablets on desire to smoke. Psychopharmacology (Berl). (1999) 147(3): 319-21.]] However, a randomized study has shown no effect on abstinence [[West R, May S, McEwen A, McRobbie H, Hajek P, Vangeli E. A randomised trial of glucose tablets to aid smoking cessation. Psychopharmacology (Berl). (2010) 207(4): 631-5]]. This shows that hypoglycemia is not a factor in tobacco addiction, although its correction by glucose is beneficial to alleviate the withdrawal effects. Back to top -*[Relaxation<-]Relaxation A majority of smokers say that smoking relaxes them, which seems paradoxical as it contrasts with the effect of adrenergic central stimulation, as seen in the stress which, as this term suggests, increases on the contrary the muscle tension by stimulating the facilitatory reticulo-spinal tract. This phenomenon is known as the « Nesbitt paradox », which has received numerous interpretations, but no fully satisfactory either [[Nesbitt PD: Smoking, physiological arousal, and emotional response. J. of Personality and Social Psychol. (1973)25: 137-44]]. In fact, the answer was already been given before the Nesbitt’s publication. [[Domino EF, Von Baumgarten AM : Tobacco, cigarette smoking and patella reflex depression.Clin. Pharmacol. Ther. (1969) 10 : 72-9]] . Nicotine directly stimulates the Renshaw’s interneuron in the anterior horn of the spinal cord. This results in an inhibition of α motor neurons, which would normally respond by an increase of muscular tone to the contraction of muscle spindles induced by the reticular stimulation by nicotine. This results in a drop in muscle tone, a real relaxation perceived by the smoker. This relaxation originates from the spinal cord, contrasting with the brain stimulation. This effect, particularly in stressed individuals, can be felt by the smoker as a benefit, and also explain the initial positive effects of nicotine in the early abstinence. However, by its brain action, nicotine maintains anxiety and stress, but they tend to mitigate off after quitting [[West R, Hajek P. What happens to anxiety levels on giving up smoking. Am J Psychiatry. (1997) 154(11): 1589-92]]. Back to top [system<-]
Nicotine and brain reward system
The existence of a reward system has triggered a lot of work on the relations between products that generate dependency, especially the nucleus accumbens [[Olds J., Milner P. Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain. J. Comp. Physiol. Psychol., (1954) 47: 419-427]]. In fact, almost all known drugs stimulate these brain structures, often intensively. Of course tobacco dependence was thus explained by the fact that, like other drugs, nicotine stimulates these areas, and many explanatory diagrams were published in the popular press. However, stimulation by nicotine is very low compared to amphetamine and cocaine. It is very difficult to obtain self-administration by rats. I have been trying for years unsuccessfully, while I was getting it easily with cocaine. We can do it by subterfuges only, nicotine replacing a reinforcer having already led to addiction, and in selected strains of rats. To extend to human smoking an animal model where dopamine secretion in the nucleus accumbens varies, depending on the species and strain, may not be sufficiently justified [[Domino EF: Conflicting evidence for the dopamine release theory of nicotine/tobacco dependence. Nihon Shinkei Seishin Yakurigaku Zasshi. (2002) 22(5): 181-4]]. In Man indeed, studies of dopamine release in the striatum under the influence of nicotine do not yield such clear-cut results. There was no overall difference in the concentration of dopamine in any explored striatum areas under the influence of nicotine. However, individual changes in dopamine concentration were correlated with subjective pleasant feelings (joy, fun), suggesting that dopamine may however play a role in the effects of nicotine [[Montgomery AJ, Lingford-Hughes AR, Egerton A, Nutt DJ, Grasby PM. The Effect of Nicotine on striatal Dopamine Release in Man: A [11C] raclopride PET Study. Synapse (2007) 61:637-645]] On the opposite, a more interesting path seems to be the effects of nicotine on the structures involved in the response to stimuli to smoke, amygdala and cingulate cortex [[Zhang X, Chen X, Yu Y, Sun D, Ma N, He S, Hu X, Zhang D . Masked smoking-related images modulate brain activity in smokers. (Hum. Brain Mapp) (2009) 30(3): 896-907]] and on the structures of memorization of such as the hippocampus [[Kenneth JW, Gould TJ Modulation of hippocampus-dependent learning and synaptic plasticity by nicotine. Mol. Neurobiol.(2008)38(1): 101-21]]. Thus could be interpreted the remarkable results of my former PhD student Caroline Cohen. Having obtained that rats self-administer nicotine intravenously, she associated an audiovisual stimulus to pressure of the active lever, but half of the rats no longer received nicotine. While receiving saline only, this group quickly stopped pressing the lever, showing that the visual stimulus was not sufficient to maintain the self-administration behavior. After a while, she suppressed the nicotine in the first group. No longer receiving nicotine, rats kept on pressing the lever, with increasing frequency, for a period exceeding three months, where she stopped the experiment [[Cohen C, Perrault G, Griebel G, Soubrié P. Nicotine-associated cues maintain nicotine-seeking behavior in Rats several weeks after nicotine withdrawal: Reversal by the cannabinoid (CB1) receptor antagonist, Rimonabant (SR141716) Neuropsychopharmacology. (2005) (1): 145-55]]. So nicotine has been shown necessary for taking up the behavior, but it persisted in its absence, as if nicotine had engraved in the memory the associated stimulus. This allows to lighten observations, in which abstinent smokers prefer cigarettes without nicotine to nicotine gums [[Johnson MW, Bickel WK, Kirshenbaum AP. Substitutes for tobacco smoking: a behavioral economic analysis of nicotine gum, denicotinized cigarettes, and nicotine-containing cigarettes. Drug Alcohol Depend. (2004)74(3): 253-64]], and probably why some ex-smokers are happy with electronic cigarettes that do not contain nicotine. Back to top [Conclusion<-]
Unfortunately we do not have any medication efficient enough to be recommended, whether the nicotine in all its forms, bupropion (Zyban) or varenicline (Champix). The level of evidence of their effectiveness is very low and subject to criticism. Doctors are formatted and almost obliged to prescribe these products because of biased scientific literature and opinion leaders bound by conflicts of interest, and by the demand of a population conditioned by large audience magazines and advertising. The role of health authorities is to provide objective information on these products, whose efficiency is hardly more than a placebo effect, but with financial consequences which unnecessarily burden family budgets and Health Insurance. A serious analysis seems unable to conclude otherwise than that the benefit/cost or risk ratio is very low. This is the reason why we ask you, Mr President, to be particularly attentive to the composition of the commission and the objectivity and independence of its work. I must add that it may be difficult for you to find independent experts in the field of smoking, which has been for years very infiltrated by the marketing agents of pharmaceutical firms.
Sincerely, Robert MOLIMARD In accordance with Article L4113-13 CSP, I declare to be free of links of interest with companies and establishments producing or operating health care products or
counseling agencies working on these products. – A more complete statement of interest is available at this page. – As my complete statement of interest is written in french (available at this page) , I declare that I had before 1998 some links with the pharmaceutical and tobacco industries, that ended since that time. Acknowledgements : _ I am very grateful to Mr. Christophe HUETTE for very careful revision of my translation.