A leszokás támogatás farmakoterápiája Dr. Horváth Éva LHS Consulting kft eva.horvath@lhs.hu Dr. Horváth Éva, A leszokás támogatás farmakoterápiája, 2004. november 27.

A dohányzás abbahagyását segítő farmakológiai megoldások Gyógyteák Nicobrevin kapszula Nikotin Pótló Terápia Bupropion SR Egyéb próbálkozások There are many different approaches to stopping smoking and they vary in their effectiveness.1 Strategies may be used alone or several combined simultaneously. Non-pharmacological approaches may be beneficial to some smokers but when used alone have a limited success rate.1-7 Until now, the only licensed pharmacological treatment has been nicotine replacement therapy (NRT), which involves substituting one form of nicotine delivery for another (i.e. patches or gum for cigarettes).8 Zyban is a new non-nicotine pharmacological treatment for smoking cessation from Glaxo Wellcome, more details of which follow later in the slides. Dr. Horváth Éva, A leszokás támogatás farmakoterápiája, 2004. november 27. 1. Parrott S, Godfrey C, Raw M et al. Thorax 1998; 53 (Suppl 5): S1-38. 2. Abbot NC, Stead LF, White AR et al. Hypnotherapy for smoking cessation (Cochrane review). In: The Cochrane Library Issue 3. Oxford: Update Software, 1999. 3. Lancaster T, Stead LF. Self-help interventions for smoking cessation (Cochrane review). In: The Cochrane Library Issue 3. Oxford: Update Software, 1999. 4. Silagy C, Ketteridge S. Physician advice for smoking cessation (Cochrane review). In: The Cochrane Library Issue 3. Oxford: Update Software, 1999. 5. Lancaster T, Stead LF. Individual behavioural counselling for smoking cessation (Cochrane review). In: The Cochrane Library Issue 3. Oxford: Update Software, 1999. 6. Stead LF, Lancaster T. Group behaviour therapy programmes for smoking cessation (Cochrane review). In: The Cochrane Library Issue 3. Oxford: Update Software, 1999. 7. White AR, Rampes H. Acupuncture for smoking cessation (Cochrane review). In: The Cochrane Library Issue 3. Oxford: Update Software, 1999. 8. Thompson GH, Hunter DA. Ann Pharmacother 1998; 32: 1067-75.

A nikotin erős addikciót okoz I. A nikotin erős addikciót okoz, erősebb, mint a kábítószerekhez (heroin vagy a kokain) való kötődés Az addikció betegségnek minősül, az orvosi gyakorlatban gyógyításához farmakoterápiás kezelést is alkalmaznak A dohányfüggőség krónikus állapot, mely ismételt beavatkozást igényel Most smokers do not continue to smoke out of choice but because they are addicted to nicotine.1 Nicotine addiction is extremely powerful. The February 2000 report of the Tobacco Advisory Group of the Royal College of Physicians stated that nicotine is highly addictive, to a degree similar to, or in some respects exceeding addiction to heroin or cocaine.1 Nicotine addiction is formally classified as a medical disease. Tobacco dependence is contained in the World Health Organization’s International Classification of Diseases, 10th Revision (ICD-10).2 Both substance dependence and nicotine withdrawal are classified as disorders according to the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV).3 The latest research into the biology of addiction indicates that nicotine addiction, like other drug addictions, has a neurobiological basis involving dopaminergic and noradrenergic systems in the brain.4 The nicotine-addicted brain is neurobiologically different from the non-addicted brain.4 The power and nature of nicotine addiction is such that attempts at smoking cessation frequently fail.5,6 Willpower is important for smoking cessation but rarely enough on its own: at least 97% of people who try to quit smoking unaided fail to do so.7,8 Dr. Horváth Éva, A leszokás támogatás farmakoterápiája, 2004. november 27. 1. Royal College of Physicians of London. Nicotine addiction in Britain: A Report of the Tobacco Advisory Group of the Royal College of Physicians. London: Royal College of Physicians, 2000. 2. World Health Organization. International statistical classification of diseases and related health problems (tenth revision, volume 1, ICD-10). Geneva: World Health Organization, 1992. 3. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (fourth edition, DSM IV). Washington, DC: American Psychiatric Association, 1994. 4. Leshner AI. Hosp Pract. 1996; Oct 15: 47-59. 5. Stapleton J. Stat Methods Med Res 1998: 7: 187-203. 6. Benowitz NL. N Engl J Med 1988; 319: 1318-30. 7. Parrott S, Godfrey C, Raw M et al. Thorax 1998; 53 (Suppl 5): S1–38. 8. Hughes JR, Gulliver SB, Fenwick JW et al. Health Psychol 1992; 11: 331-34.

A nikotin addikcióban szerepet játszó neurotranszmitterek Sóvárgás / késztetés a mezolimbikus rendszerben (Módosítja a dopamin felszabadulást) Elvonás a locus coeruleusban (Megváltoztatja a noradrenerg aktivitást) The precise mechanism by which bupropion HCl SR enhances the ability of patients to abstain from smoking is not established. However, it does not involve substituting one form of nicotine delivery for another. Bupropion HCl SR is a relatively weak but selective inhibitor of the neuronal reuptake of dopamine and noradrenaline, with very minimal effect on serotonin and does not inhibit monoamine oxidase.1 As an aid to smoking cessation, bupropion HCl SR is believed to work directly on two pathways in the brain that are important in the addiction process through its dopaminergic and noradrenergic properties. The dopaminergic activity of bupropion is thought to affect the area of the brain implicated in the positive reinforcing properties of addictive drugs and the development of dependence – the ‘reward’ pathway.2,3 Its noradrenergic effects in the locus coeruleus – the ‘withdrawal’ pathway - are thought to play a role in withdrawal from nicotine.2,3 Dr. Horváth Éva, A leszokás támogatás farmakoterápiája, 2004. november 27. 1. Ascher JA, Coles JO, Colin J-N et al. J Clin Psychiatry 1995; 56: 395-401. 2. Covey LS, Sullivan MA, Johnston JA et al. Drugs 2000; 59 (1): 17-31. 3. Ferry LH. Primary Care Clinics in Office Practice 1999; 26 (3): 653-69.

Konvenciók A dohányosok úgy gondolják, hogy a dohányzás abbahagyásakor a kritikus és a legfontosabb tényező az akaraterő és a kitartás. A segéd-eszközök használata megkérdőjelezi ezt az erőt és a gyengeség jeleként érzékelik. Világszerte a leggyakrabban alkalmazott módszer az akaraterő önmagában, pedig ez a legkevésbé hatékony! Változtassunk ezen a hozzáálláson! Értessük meg betegeinkkel, hogy a gyógyszerek használata nem a gyengeség jele, hanem azok tovább fokozzák akaraterejüket ! Dr. Horváth Éva, A leszokás támogatás farmakoterápiája, 2004. november 27.

Nikotin Pótló Terápia A nikotinról történő elválasztáson alapul Biztonságosabb, mint a dohányfüst Nem rákkeltő Nem receptköteles NRT addresses the problem of smoking addiction by ‘weaning’ the patient off nicotine through step-wise reductions in dose size or frequency over time, while helping to decrease the severity of nicotine withdrawal symptoms.1 Different formulations are available such as gum, patch, nasal spray, inhalator, sub-lingual tablet and most recently, a lozenge. The choice of which form is used should reflect patient needs, tolerability and cost considerations.2,3 Nevertheless, they all have similar efficacy, increasing the chance of stopping by 1.6- to 2.3-fold (over placebo or no intervention) as the following slide illustrates.3 When combined with intensive support, about one in five smokers who try to stop with the aid of NRT remain abstinent for a year.4 With NRT, patients should set a date for stopping smoking and start treatment on this day. Patients who do not stop successfully with NRT during the first one to two weeks of treatment are unlikely to succeed on this attempt.5-7 Dr. Horváth Éva, A leszokás támogatás farmakoterápiája, 2004. november 27. 1. Silagy et al, The Cochrane Library 1999. 1. Thompson GH, Hunter DA. Ann Pharmacother 1998; 32: 1067-75. 2. National Prescribing Centre. Nicotine replacement therapy. MeReC Bulletin 1999; 10 (3): 9-12. 3. Silagy C, Mant D, Fowler G et al. Nicotine replacement therapy for smoking cessation (Cochrane review). In: The Cochrane Library. Issue 3. Oxford: Update Software, 1999. 4. Parrott S, Godfrey C, Raw M et al. Thorax 1998; 53 (Suppl 5): S1-38. 5. Kenford SL, Fiore MC, Jorenby DE et al. J Am Med Assoc 1994; 271: 589-94. 6. Tonneson P, Paoletti P, Gustavsson G et al. Eur Respir J 1999; 13: 238-46. 7. Yudkin PL, Jones L, Lancaster T, Fowler GH. Br J Gen Pract 1996; 46: 145-48.

Nikotin Pótló Terápia Magyarországon Nicorette 2mg 7x15 , Mint 2mg x 105 rágógumi (1988, 1998) Pfizer Nicotinell TTS 10, 20, 30 x 7 tapasz (1992) Novartis Consumer Health Nicotinell Fruit 2mg x 12/48, Mint 2mg x 12/48 rágógumi (2000) Novartis Consumer Health NiQuitin CQ tapasz 7, 14, 21 mg (2003) GlaxoSmithKline NiQuitin CQ mentolos szopogató tabletta 2, 4mg (2005) GlaxoSmithKline Nicotinell Mint szopogató tabletta 1 mg (2005) Novartis Consumer Health NRT addresses the problem of smoking addiction by ‘weaning’ the patient off nicotine through step-wise reductions in dose size or frequency over time, while helping to decrease the severity of nicotine withdrawal symptoms.1 Different formulations are available such as gum, patch, nasal spray, inhalator, sub-lingual tablet and most recently, a lozenge. The choice of which form is used should reflect patient needs, tolerability and cost considerations.2,3 Nevertheless, they all have similar efficacy, increasing the chance of stopping by 1.6- to 2.3-fold (over placebo or no intervention) as the following slide illustrates.3 When combined with intensive support, about one in five smokers who try to stop with the aid of NRT remain abstinent for a year.4 With NRT, patients should set a date for stopping smoking and start treatment on this day. Patients who do not stop successfully with NRT during the first one to two weeks of treatment are unlikely to succeed on this attempt.5-7 Dr. Horváth Éva, A leszokás támogatás farmakoterápiája, 2004. november 27. 1. Thompson GH, Hunter DA. Ann Pharmacother 1998; 32: 1067-75. 2. National Prescribing Centre. Nicotine replacement therapy. MeReC Bulletin 1999; 10 (3): 9-12. 3. Silagy C, Mant D, Fowler G et al. Nicotine replacement therapy for smoking cessation (Cochrane review). In: The Cochrane Library. Issue 3. Oxford: Update Software, 1999. 4. Parrott S, Godfrey C, Raw M et al. Thorax 1998; 53 (Suppl 5): S1-38. 5. Kenford SL, Fiore MC, Jorenby DE et al. J Am Med Assoc 1994; 271: 589-94. 6. Tonneson P, Paoletti P, Gustavsson G et al. Eur Respir J 1999; 13: 238-46. 7. Yudkin PL, Jones L, Lancaster T, Fowler GH. Br J Gen Pract 1996; 46: 145-48.

A rágógumi adagolása Adagolás: Induláskor általában napi 8-12 rágógumira van szükség, később fokozatosan csökkenteni kell Napi maximum: 25 db A szopogató tabletta adagolása Adagolás lépcsőzetesen: 1- 6 hétig 1 tbl/1-2 óra 7- 9 hétig 1 tbl/2-4 óra 10-12 hétig 1 tbl/4-8 óra Napi maximum: 16 db Dr. Horváth Éva, A leszokás támogatás farmakoterápiája, 2004. november 27.

A tapasz adagolása, használata 24 óránként 1 tapasz Napi több, mint 20 cigaretta esetén/rágyújtás 30 percen belül az ébredés után: indítás a legerősebb tapasszal 4 hétig, majd a közepes tapasszal további 4 hétig Napi <20 cigaretta esetén/rágyújtás ébredés után több mint 30 perccel: indítás a közepes tapasszal 8 hétig Végül mindenkinek a legkisebb tapasz 4 héten át Dr. Horváth Éva, A leszokás támogatás farmakoterápiája, 2004. november 27.

Megfontolandók nikotin pótlásban részesülő pácienseknél Aluldozírozás, rendszertelen használat, dohányzás folytatása Terápia túl korai abbahagyása / folyamatos hosszú távú használat Tapasz használatakor lassabban és kevésbé hatékonyan jut be a nikotin, mint a cigarettából Nem mindenkinek megfelelő While NRT is effective in some patients, there are some considerations to its use. Smokers’ use of NRT is variable. For example, there is a tendency to under-dosing or irregular usage1,2 while some patients may smoke cigarettes concurrently despite instructions not to.1 Other patients may discontinue treatment prematurely3 or continue to use it long-term.3-6 In general, NRT products are a slower and less efficient source of nicotine compared with inhalation of cigarette smoke.2,3 In addition, some smokers worry that they will transfer their dependence from cigarettes to NRT.7,8 Indeed, there is some evidence suggesting that this might occur with certain presentations.5,9-11 Finally, NRT is not suitable for all patients.12 Dr. Horváth Éva, A leszokás támogatás farmakoterápiája, 2004. november 27. 1. Fant RV, Owen LL, Henningfield JE. Primary Care Clin Office Pract 1999; 26: 633-52. 2. Rennard SI, Daughton DM. J Resp Dis 1998; 19 (Suppl 8): S20-25. 3. Benowitz NL. Drugs 1993; 45: 157-70. 4. Hajek P, Jackson P, Belcher M. J Am Med Assoc 1988; 260: 1593-96. 5. Sutherland G, Stapleton JA, Russell MAH et al. Lancet 1992; 340: 324-29. 6. Hjalmarson A, Franzon M, Westin A, Wiklund O. Arch Intern Med 1994; 154: 2567-72. 7. Anon. Nicotine replacement to aid smoking cessation. Drug Therap Bull 1999; 37: 52-54. 8. Hughes JR. J Drug Dev 1994; 6: 197-203. 9. Hughes JR. Biomed Pharmacother 1989; 43: 11-17. 10. Hughes JR, Hatsukami DK, Skoog KP. J Am Med Assoc 1986; 255: 3277-79. 11. West R, Russell MAH. Psychol Med 1985; 15: 891-93. 12. Thompson GH, Hunter DA. Ann Pharmacother 1998; 32: 1067-75.

Nem nikotinos farmakoterápiás megoldás: a Bupropion SR Adagolás: Induláskor, 3-4 napig reggel napi 1 tabletta, majd napi 2x1 tabletta a terápia végéig Dohányzás abbahagyása a 8-15 nap között Dr. Horváth Éva, A leszokás támogatás farmakoterápiája, 2004. november 27.

Ellenjavallat Mellékatások Túlérzékenység a hatóanyaggal szemben Epilepszia Bulimia, anorexia nervosa MAO bénítókkal együtt nem adható Mellékatások Alvászavar Fejfájás Szájszárazság A mellékhatások általában enyhék és átmeneti jellegűek Dr. Horváth Éva, A leszokás támogatás farmakoterápiája, 2004. november 27.

Összehasonlító vizsgálat Pont prevalencia 1 év után 40 30 20 10 * † 35.5% p <0.001 vs placebo † p <0.001 vs nikotin tapasz * * † 30.3% % az absztinensek aránya 16.4% 15.6% The primary efficacy variable in the comparative study was point prevalence smoking abstinence at 6 and 12 months. Point prevalence abstinence rates at 1 year indicated that bupropion HCl SR-treated patients were almost twice as successful in achieving smoking abstinence than those who received placebo (30.3% vs. 15.6%; p<0.001) and those who received the nicotine patch (30.3% vs. 16.4%; p<0.001).1 This means that every 1 in 3 patients treated with bupropion HCl SR was not smoking at 1 year.1 Although the quit rates in the bupropion HCl SR plus nicotine patch group were slightly higher than in the bupropion HCl SR alone group (35.5% vs. 30.3%), no statistically significant difference was observed.1 The high placebo value of 15.6% might be accounted for by the fact that it was a double-dummy study and that patients in this treatment arm received a placebo patch and placebo tablets. The figure of 16.4% for the nicotine patch group is consistent with the Cochrane review, which found an overall abstinence rate for NRT of 17% at 12 months—13% (CI 12% to 14%) for nicotine patches specifically.2 Based on the results of the comparative study, numbers-needed-to-treat (NNTs) to achieve a quitter at 1 year have been calculated using the formula outlined by Bandolier3 as follows: – Zyban plus support compared with placebo plus support = 6.8 – Zyban plus support compared with nicotine patch plus support = 7.2 – Zyban and NRT combination plus support compared with placebo plus support = 5.2 – Zyban and NRT combination plus support compared with nicotine patch plus support = 5.2. Placebo (n=160) Nikotin tapasz 21 mg/nap (n=244) Bupropion SR 300 mg/nap (n=244) Bupropion SR + Nikotin tapasz (n=245) Dr. Horváth Éva, A leszokás támogatás farmakoterápiája, 2004. november 27. Jorenby et al, N Engl J Med 1999. 1. Jorenby DE, Leischow SJ, Nides MA et al. N Engl J Med 1999; 340: 685-91. 2. Silagy C, Mant D, Fowler G et al. Nicotine replacement therapy for smoking cessation (Cochrane review). In: The Cochrane Library. Issue 3. Oxford: Update Software, 1999. 3. Bandolier website: http:www.ebando.com/band59/NNT1.html

Vizsgálati eredmények Szignifikánsan csökken a dohányzás utáni sóvárgás és az elvonási tünetek (pl. szorongás, koncentrálási nehézségek, nyugtalanság, frusztráció) Szignifikánsan kisebb súlygyarapodás, mint placebo esetén Kedvező kardiovaszkuláris tolerabilitási profil A bupropion SR jól tolerálható Minden 3 bupropionnal kezelt páciens közül 1 még 1 év múlva sem dohányzott (30.3%) Nikotinpótló készítményekkel biztonsággal kombinálható Cravings, or urges to smoke, and unpleasant withdrawal symptoms are major obstacles facing smokers trying to stop. 1,2 Reducing cravings and withdrawal symptoms can therefore help towards success in smoking cessation by making quitting more bearable for the patient. Treatment with bupropion HCl SR was associated with a reduction in cigarette craving,3,4 or the urge to smoke, compared with placebo,5 reaching statistical significance at several time points during treatment. Treatment with bupropion HCl SR was also found to reduce nicotine withdrawal symptoms compared with placebo.5,6 Reductions in irritability, frustration or anger, and in anxiety, difficulty concentrating, and restlessness were most pronounced and reached statistical significance over placebo at most times during treatment.5 Fear of weight gain prevents many smokers from attempting to quit and weight gain itself is a common reason for relapse following a quit attempt.7,8 Bupropion HCl SR patients gained significantly less weight during the course of treatment than those on placebo.9,10 For patients in the dose-response study who were continuously abstinent from the stop date through to the end of treatment, mean weight gain at the end of treatment was 1.5 kg in the bupropion HCl SR 300 mg/day group compared with 2.9 kg for placebo. 9 However, it is important to point out that bupropion HCl SR is not licensed for use in the treatment of obesity or for weight loss. Dr. Horváth Éva, A leszokás támogatás farmakoterápiája, 2004. november 27. 1. Killen JD, Fortmann SP, Newman B, Varady A. Psychopharmacol 1991; 105: 191-96. 2. West R, Schneider. Br J Addiction 1987; 82: 407-15. 3. Glaxo Wellcome, data on file (study 403). 4. Grasela T, Glover E, Sachs DPL, Johnston JA. Collegium International Europsychopharmacologicum Glasgow, July 1998 (Abstract). 5. Glaxo Wellcome, data on file (study 405). 6. Jorenby DE, Leischow SJ, Nides MA et al. N Engl J Med 1999; 340: 685-91. 7. Carmody TP. J Psychoactive Drugs 1992; 24: 131-58. 8. Sachs DPL, Leischow SJ. Clin Chest Med 1991; 12 (4): 769-91. 9. Hurt RD, Sachs DPL, Glover ED et al. N Engl J Med 1997; 337: 1195-202. 10. Glaxo Wellcome, data on file (weight change analyses from studies 403 & 405).

Egyéb nem nikotinos farmakoterápiás megoldások Nortriptilin – triciklikus antidepresszáns, bizonyított a hatékonysága, mellékhatás profilja miatt csak második vonalbeli terápiaként alkalmazható a bupropion és a NPT után Clonidin – hatékony, de mellékhatásai korlátozzák használhatóságát Rimonabant – új hatásmechanizmus, ópiát rendszeren keresztül hat, még nincs forgalomban Dr. Horváth Éva, A leszokás támogatás farmakoterápiája, 2004. november 27.

Konklúzió I. A nikotin erősen addiktív A nikotin okozta addikciónak neurobiológiai alapjai vannak Ezért farmakoterápiára is szükség van Fogadtassuk el a páciensekkel a segédeszközök szükségességét Hatékony és biztonságos gyógyszerek vannak forgalomban Smoking cessation is a highly cost-effective healthcare intervention, comparing favourably with many other common healthcare interventions.1,2 To be successful, smoking cessation strategies need to address the overriding role of nicotine addiction in keeping smokers smoking, as well as the behavioural aspects of the disorder.3 For this reason, the more effective approaches to smoking cessation involve simultaneously targeting of both aspects, using pharmacological intervention combined with some form of motivational support and advice.4,5 It is well accepted that advice from a healthcare professional, even if brief, can increase smoking cessation rates.6 NRT can also help some smokers to stop smoking by reducing nicotine withdrawal symptoms through weaning schedules; however, there are some considerations to its use.4,7-9 The availability of new, effective and alternative pharmacological treatments for smoking cessation are clearly needed and will provide further impetus for healthcare professionals to help those smokers who are motivated to stop. Dr. Horváth Éva, A leszokás támogatás farmakoterápiája, 2004. november 27. 1. Parrott S, Godfrey C, Raw M et al. Thorax 1998; 53 (Suppl 5): S1-38. 2. Briggs AH, Gray AM. Health Technol Assess 1999; 3: 1-134. 3. Leshner AI. Hosp Pract 1996; Oct 15: 47-59. 4. Thompson GH, Hunter DA. Ann Pharmacother 1998; 32: 1067-75. 5. Haxby DG. Treatment of nicotine dependence. Am J Health Sys Pharm 1995; 52: 265-81. 6. Raw M, McNeill A, West R. Thorax 1998; 53 (Suppl 5): S1-19. 7. Fant RV, Owen LL, Henningfield JE. Primary Care Clin Office Pract 1999; 26 (3): 633-52. 8. Rennard SI, Daughton DM. J Resp Dis 1998; 19 (Suppl 8): S20-S25. 9. Benowitz NL. Drugs 1993; 45: 157-70.

Konklúzió II. A leszokást segítő farmakoterápiás készítmények egymással kombinálhatók, fokozzák egymás hatását A segítséget kérő, motivált páciens ne „lépcsőzetes” kezelést kapjon, hanem kapja meg a maximális segítséget már az elején A leghatékonyabb módszer motivált pácienseknél: tanácsadás és gyógyszeres kezelés együttesen Smoking cessation is a highly cost-effective healthcare intervention, comparing favourably with many other common healthcare interventions.1,2 To be successful, smoking cessation strategies need to address the overriding role of nicotine addiction in keeping smokers smoking, as well as the behavioural aspects of the disorder.3 For this reason, the more effective approaches to smoking cessation involve simultaneously targeting of both aspects, using pharmacological intervention combined with some form of motivational support and advice.4,5 It is well accepted that advice from a healthcare professional, even if brief, can increase smoking cessation rates.6 NRT can also help some smokers to stop smoking by reducing nicotine withdrawal symptoms through weaning schedules; however, there are some considerations to its use.4,7-9 The availability of new, effective and alternative pharmacological treatments for smoking cessation are clearly needed and will provide further impetus for healthcare professionals to help those smokers who are motivated to stop. Dr. Horváth Éva, A leszokás támogatás farmakoterápiája, 2004. november 27. 1. Parrott S, Godfrey C, Raw M et al. Thorax 1998; 53 (Suppl 5): S1-38. 2. Briggs AH, Gray AM. Health Technol Assess 1999; 3: 1-134. 3. Leshner AI. Hosp Pract 1996; Oct 15: 47-59. 4. Thompson GH, Hunter DA. Ann Pharmacother 1998; 32: 1067-75. 5. Haxby DG. Treatment of nicotine dependence. Am J Health Sys Pharm 1995; 52: 265-81. 6. Raw M, McNeill A, West R. Thorax 1998; 53 (Suppl 5): S1-19. 7. Fant RV, Owen LL, Henningfield JE. Primary Care Clin Office Pract 1999; 26 (3): 633-52. 8. Rennard SI, Daughton DM. J Resp Dis 1998; 19 (Suppl 8): S20-S25. 9. Benowitz NL. Drugs 1993; 45: 157-70.

Köszönöm szépen a figyelmet! Dr. Horváth Éva, A leszokás támogatás farmakoterápiája, 2004. november 27.