|
 
 |
| REVIEW ARTICLE |
|
| Year : 2019 | Volume
: 11
| Issue : 1 | Page : 41-47 |
|
An update on nicotine replacement therapy
KA Kamala1, S Sankethguddad2, SG Sujith2
1 Department of Oral Medicine and Radiology, School of Dental Sciences, KIMSDU, Karad, Maharashtra, India
2 Department of Periodontology, Shivtej Arogya Seva Sanstha's Yogita Dental College and Hospital, Ratnagiri, Maharashtra, India
| Date of Submission | 23-May-2018 |
| Date of Acceptance | 03-Nov-2018 |
| Date of Web Publication | 6-Mar-2019 |
Correspondence Address:
K A Kamala
Department of Oral Medicine and Radiology, School of Dental Sciences, KIMSDU, Karad, Satara - 415 110, Maharashtra
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/jorr.jorr_9_18
Tobacco use is the single greatest preventable cause of death in the world. Most tobacco users want to quit but find it difficult to stop due to the addictiveness of nicotine. Interventions for tobacco cessation are important in enabling tobacco users to stop using, which includes pharmacological and nonpharmacological approaches to aid tobacco cessation. Pharmacological approaches include nicotine replacement therapy (NRT) and nonnicotine medications (bupropion and varenicline). NRT delivers nontoxic forms of nicotine to help tobacco user's deal with nicotine cravings and maintains stimulation of the nicotine receptors. Forms of delivery for NRT include the following: nicotine chewing gum, nicotine lozenge, transdermal patch, nicotine inhaler, nicotine nasal spray, and nicotine sublingual tablets. These NRTs are in general well tolerated and have minimal adverse effects. The present review gives an overview about various modes of NRT methods currently used to treat nicotine dependence.
Keywords: Addiction, nicotine, nicotine replacement therapy
How to cite this article:
Kamala K A, Sankethguddad S, Sujith S G. An update on nicotine replacement therapy. J Oral Res Rev 2019;11:41-7 |
| Introduction | |  |
Tobacco smoking is globally far more widespread than the use of any other form of substance abuse.[1] Its use remains the leading preventable cause of morbidity and mortality, each year causing more than 6 million deaths globally.[2] The World Health Organization estimates that there are 1.3 billion smokers worldwide, and each year 5 million smokers die because of tobacco-related diseases.[3] Data suggest that up to 70% of current smokers want to quit and 40% attempt to do so each year.[2] Madiyal A et al.[4] carried out a cross-sectional questionnaire-based survey among 550 smokers from South India to assess the knowledge and attitude toward health effects of smoking and their intentions to quit. The incidence was highest in men from rural areas with low education women from urban areas with a high level of education. The habit of smoking in men is mainly to distress while in females to socialize and majority of them were aware of the ill effects of smoking on health and were willing to quit the habit. Approximately, a third of current smokers attempt to quit smoking each year in England, but even effective behavioral interventions, such as those provided in the UK Stop-Smoking Services, yield less than one in six successful long-term ex-smokers. Population studies suggest that motivation to quit is an important predictor of quit attempts. This indicates that identification of processes that enable change in the salience of motivation to quit is of key importance for the development of effective health promotion interventions.[5]
Of the 4000 chemicals identified in tobacco smoke, nicotine is the main active ingredient in tobacco products, which is highly toxic and potentially lethal that reinforces the individual to tobacco addiction behavior. Nicotine is mostly absorbed through the buccal mucosa, and the absorption rate depends on the route of administration such as cigarette smoking and inhalation. The drug is metabolized by the liver, lungs, and kidneys, and about 10% is excreted through the urine without any change.[6]
Nicotine replacement therapy (NRT) replaces nicotine obtained from cigarettes to reduce withdrawal symptoms associated with smoking cessation, thus helping resist the urge to smoke cigarettes.[7] NRT aims to reduce motivation to consume tobacco and the physiological and psychomotor withdrawal symptoms through the delivery of nicotine.[6] NRT provides lower and slower increasing plasma nicotine concentrations, without exposure to toxic combustion products and is considered safe, including in combination form or if used while smoking.[2] The relative benefit of NRT on smoking cessation is independent of delivery method, definition of abstinence, length of treatment, level of supportive counseling, treatment venue (hospital, clinic, and support group), and whether a fixed, variable or tapered dose is used.[6] NRT is available in a variety of forms including chewing gums, patches, tablets, inhalers, and sprays.[8]
| Mechanism of Action of Nicotine | | |
Nicotine acts by the stimulation of neural nicotinic acetylcholine receptors (nACh receptors) in the ventral tegmental area of the brain. Stimulation of nACh receptors also leads to the activation of the central, peripheral nervous system, and nonneuronal tissue. This causes the release of dopamine in the nucleus accumbens. Consequently, nicotine exposure affects numerous systems, including neurological, neuromuscular, cardiovascular, respiratory, immunological, and gastrointestinal. This leads to a reduction in nicotine withdrawal symptoms in regular smokers who abstain from smoking.[2],[9] The presence of different types of nACh receptors, receptor upregulation, and receptor desensitization influences these complex physiological effects.[10]
| Mechanism of Nicotine Addiction | | |
Nicotine is a small molecule (162 Da) and indicated by its chemical name, (S)-3-(1-Methylpyrrolidin-2-yl) pyridine. It contains a pyridine and a pyrrolidine ring, both of which carry a tertiary amine. The two rings possess different acid dissociation constants, producing a net acid dissociation constant (pKa) of 8.0–8. The average nicotine content of a cigarette is 10–14 mg, only 10% of which enters the systemic circulation, resulting in peak plasma concentrations of 300–500 nM. The amount of nicotine binding to plasma proteins is negligible (5%); its half-life is about 2 h, and the greater part of nicotine is metabolized to cotinine by cytochrome P450 (CYP) isoenzyme (CYP2A6).[3],[11]
Inhaled nicotine from tobacco smoke enters the circulation through the lungs. The accumulation of the nicotine in the brain starts approximately 7 s after inhalation. Nicotine binds to nACh receptors in the brain that leads to a release of adrenaline and dopamine. This improves mood and reinforces the behavior. Since nicotine is the main factor responsible for the addiction to cigarette smoking, its rapid rates of absorption and entry to the brain are believed to be key factors responsible for the high abuse potential of this drug.[12] Nicotine induces pleasure and reduces stress and anxiety. Smokers use nicotine to control their mood, and for arousal, it also improves concentration. When a person who is addicted to nicotine stops smoking, he experiences unpleasant withdrawal symptoms. Those symptoms include depressed mood, irritability, anxiety, and restlessness.[1],[13]
| Forms of Nicotine Replacement Therapy | | |
NRT products are available in a number of forms as follows: chewing gum, transdermal patch, nasal spray, oral inhaler, and tablet [Table 1]. Transdermal patch is a slow, sustained release form of nicotine delivery. Other products such as chewing gum, nasal spray, oral inhaler, and tablets are acute-dosing forms of nicotine. They provide general craving relief and breakthrough craving relief with immediate release of nicotine. All of these products have different levels of efficacy and variable rates of nicotine absorption, and they are most effective when the consumer also receives parallel cessation counseling and behavioral therapy.[6],[8],[10],[14],[15],[16]
Transdermal patch
Transdermal patches are a common form of NRT those are applied to the skin and deliver nicotine through the skin at a relatively steady rate. It delivers nicotine more slowly than acute NRT formulations, although nicotine plasma concentrations can get higher during the day with patch use than with acute NRT use. They are available in different doses, and deliver between 5 mg and 22 mg of nicotine over a 24-h period. Current evidence supports the safety of long-term use of nicotine patch treatment for tobacco abstinence.[2],[17] The main advantage of nicotine patches over acute NRT formulations is that compliance is simple, the patient simply places the patch on the body in the morning, rather than actively using a product throughout the day.[16] The most common reported side effects in youth are mouth and skin irritations, increased heart rates and higher blood pressure readings, and sleep disturbances.[18],[19]
Schnoll et al.[20] recruited 525 treatment-seeking smokers for a randomized clinical trial to compare 8 (standard), 24 (extended), and 52 (maintenance) weeks of nicotine patch treatment for promoting tobacco abstinence. The results of the findings support the safety of long-term use of nicotine patch treatment, although they do not support the efficacy beyond 24 weeks of treatment in a broad group of smokers.
| Acute-Dosing Nicotine Products | | |
Acute-dosing nicotine products include chewing gum, lozenge, sublingual tablet, oral inhaler, and nasal spray. Acute-dosing products have the benefit that both the amount and timing of doses can be titrated by the user. Thus, smokers with more nicotine tolerance or greater need can get a higher nicotine dose, and smokers who are experiencing acute adverse effects can scale back their intake.[6]
Nicotine chewing gum
Nicotine chewing gum was the first transmucosally delivered NRT that was made available to consumers.[21] It is not chewed like ordinary confectionary gum but is intermittently chewed and held in the mouth over about 30 min, as needed, to release its nicotine. It is available in both 2 mg and 4 mg dosage forms. Smokers that are more dependent have been shown to improve their chances of achieving abstinence with the 4-mg than the 2-mg gum. The number of doses per day is reduced gradually until it is no longer required. Acidic beverages have been shown to interfere with buccal absorption of nicotine; therefore, the patients should avoid acidic beverages (e.g., soda, coffee, and beer) for 15 min before and during chewing gum.[14],[16] Joseph et al.[22] found that extended treatment with nicotine gum, patches, or lozenges for 52 weeks significantly increased smoking cessation rates compared with 4 weeks of treatment. Lewis et al.[23] conducted study with mucoadhesive tablets of nicotine for buccal administration to evaluated it'sin vivo release pattern and pharmacokinetic. Mucoadhesive tablets for buccal administration of nicotine were prepared as an alternative to the available nicotine dosage forms. Three types of tablets were developed each containing two mucoadhesive components HPMC, K4M, and sodium alginate and HPMC, K4M, and carbopol (chitosan and sodium alginate). For each of the type, batches were produced changing the quantity of polymers resulting in nine different formulations. Authors concluded that a peak plasma concentration of 16.78 ± 2.27 ng was obtained in 2 h, which suggests potential clinical utility in NRT.
Nicotine lozenge
The lozenge is available in 2 and 4 mg formulations. It dissolves in the mouth over approximately 30 min. As with nicotine gum, nicotine from the lozenge is absorbed slowly through the buccal mucosa and delivered into systemic circulation. The lozenge provides an alternative to the gum for persons who need intermittent and controllable nicotine dosing but who do not find gum chewing acceptable. The amount of nicotine absorbed per lozenge appears to be somewhat higher than that delivered by gum.[6],[14]
Nicotine sublingual tablet
It is held under the tongue where the nicotine in the tablet is absorbed sublingually. The levels of nicotine obtained by use of the 2 mg lozenge and 2 mg sublingual tablet are similar. It is recommended that smokers use the product for at least 12 weeks. After 12 weeks, the number of tablets used should be gradually tapered.[6],[16]
In a randomized, double-blind, placebo-controlled trial of 2-mg sublingual tablets, success rates for complete abstinence for active versus placebo were 50% versus 29% at 6 weeks, 42% versus 23% at 3 months, and 33% versus 18% at 6 months. This doubling of quit rates is comparable to the doubling seen with other forms of NRT.[24]
Nicotine oral inhaler
It consists of a mouthpiece and a plastic cartridge containing nicotine. Majority of nicotine from the inhaler is delivered into the oral cavity (36%), esophagus and stomach (36%), and very little to the lung (4%). The rate of absorption is similar to that of nicotine gum. Each inhaler cartridge contains 10 mg nicotine, of which up to 4 mg can be delivered and 2 mg can be absorbed following frequent “puffing.”[25] However, as with nicotine gum, success is largely dependent on the number of doses taken per day. In clinical trials, most smokers who successfully abstained from smoking used between 6 and 16 cartridges per day.[25],[26]
Nicotine nasal spray
Nicotine nasal spray was designed to deliver nicotine doses more rapidly, and it is directly absorbed into the blood. It is available to consumers in a multidose bottle with a pump mechanism fitted to a nozzle that delivers 0.5 mg of nicotine per 50-uL squirt. Each dose consists of two squirts, one to each nostril. Patients should be started with one or two doses per hour, which may be increased up to the maximum of 40 doses per day. One dose of nasal spray per hour (1 mg nicotine) for 10 h produces average plasma concentrations of 8 ng/ml.[16],[17],[26]
Electronic nicotine delivery systems/electronic cigarettes/e-cigarettes
Electronic nicotine delivery systems (ENDS) are devices whose function is to vaporize and deliver chemical mixture typically composed of nicotine to the lungs of the user. Each ENDS device contains an electronic vaporization system, rechargeable batteries, electronic controls, and cartridges of the liquid that is vaporized.[27] It delivers vaporized chemical mixture typically composed of nicotine to the lungs of the user. The liquid usually contains glycerol, propylene glycol, water, nicotine, and a variety of flavors that the user can choose. ENDS directly delivers nicotine to the upper and lower respiratory tract without any combustion involved.[28] E-cigarettes are becoming a preferred alternative for nicotine delivery among many smokers because of their realistic look, feel, and taste compared to traditional cigarettes.[27],[28]
The US Food and Drug Administration has reported that e-cigarette cartridges and solutions contain potentially harmful components, and they recommend that the sale of e-cigarettes should be prohibited or regulated as dangerous nicotine delivery systems.[29]
The current evidence suggests that ENDS are an effective smoking cessation tool, but more research is needed to confirm its long-term effectiveness and safety.[30],[31] Strasser et al.[32] conducted a study to know the better understanding, use, and exposure of using e-cigarettes. Twenty-eight cigarette smokers were randomized to use one of five popular brands of e-cigarettes for a 10-day period. Day 1 (own cigarette brand) data established baseline levels for cotinine, carbon monoxide (CO), topography, cigarette liking, withdrawal, and craving. Participants returned on days 5 and 10 to reassess these measures while exclusively using e-cigarettes. They concluded that e-cigarettes are not liked as much as cigarettes, provide significantly lower nicotine replacement, reduce CO exposure, and mitigate withdrawal and craving.
| Combined Patch Plus Acute Forms | | |
The rationale for combining NRT medications is that smokers may need both a slow delivery system to achieve a constant concentration of nicotine to relieve cravings and tobacco withdrawal symptoms, as well as a faster-acting preparation that can be administered on demand for immediate relief of breakthrough cravings and withdrawal symptoms. For example, combining transdermal patch with nicotine chewing gum, nasal spray, or inhaler. The patch provides nicotine in a steady-state and passive form while gum can be manipulated to accommodate the users' needs. Clinical trials suggest the incremental efficacy of patch plus gum compared to either product alone.[33],[34] Combining the nicotine patch with an oral form of NRT has been shown to increase quit rates by 34%–54% compared to using the patch alone.[35]
Less research is available on combinations of the patch and other acute NRT formulations. However, one study that compared the efficacy of the nicotine inhaler plus nicotine patch versus nicotine inhaler plus placebo patch for smoking cessation found a significantly higher abstinence rate at 1 year among those who used the combination.[36]
| Prequitting Nicotine Replacement Therapy or Nicotine Preloading | | |
The use of NRT before quitting smoking is called nicotine preloading. This approach involves using NRT for several weeks before quitting. The most plausible mechanisms include habituation with the use of NRT in the lead-up to quitting, attenuation of desire to smoke due to nicotine receptor saturation, and it reduces satisfaction from smoking by which it undermines the learned association between smoking and reward. A review suggests that initiating patch use for a short period before making a quit attempt is moderately more effective than patch use initiated on the quit date itself. A meta-analysis on precessation patch treatment found that it will produce a robust increase in quit rates compared to current regimens starting the patch at quit day.[31],[37]
| Nicotine Vaccines | | |
Nicotine vaccines [Table 2] represent a newer novel therapeutic concept to treat the nicotine dependence. Because nicotine is a small molecule and an incomplete antigen, it is linked to a carrier protein to stimulate the necessary immune response.[6] Nicotine vaccines can be used both for relapse prevention or as preparation for a quit attempt.[1] The mechanism of immunization against nicotine can be achieved by active or passive immunization. Active immunization refers to the administration of an immunogenic substrate that causes T- and B-cell activation, leading to the formation of specific antibodies within the studied individual. Passive immunization is defined as the administration of preformed monoclonal or polyclonal high-affinity antibodies, and it offers immediate protection.[3]
A number of organizations have developed vaccines for smoking cessation, with NicVAX developed by Nabi Biopharmaceuticals being perhaps the best known. A potential drawback of vaccines to treat tobacco dependence is the fact that smokers will often compensate for decreases in the actions of nicotine, as would be expected when a vaccine decreases concentrations of nicotine penetrating into brain tissues, by increasing their tobacco consumption to overcome this effect. Other potential issues related to the successful use of vaccines include difficulties achieving sufficiently high antibody titers, the fact that vaccines are generally short-lived and significant interindividual variation in response to the vaccine typically observed.[3],[6],[38]
| Conclusion | | |
Understanding use patterns of tobacco products is an important component of assessing the impact the product has on public health. Nicotine addiction is the major factor impeding smoking cessation and long-term abstinence. Today, several nicotine medications are available in different forms, doses, and flavors and their use has been recommended for all tobacco consumers who do not have medical contraindications. The effectiveness of NRT appears to be largely independent of the intensity of additional support, and longer courses of NRT are not demonstrably superior to shorter durations of therapy. NRTs increase the rate of quitting by 50%–70% and appear to be a safe and effective option for current smokers who wish to quit with lack of serious adverse effects. Future studies should investigate the long-term effect or the effect on preventing relapse, analyze cost-effectiveness among different smoking populations, and assess the impacts of comorbid conditions, medical history, or the strong motivation to quit. It is essential for health professionals to become familiar with all forms of NRT to be able to address the questions and needs of tobacco users who appear to be increasingly interested in tobacco cessation.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Goniewicz ML, Delijewski M. Nicotine vaccines to treat tobacco dependence. Hum Vaccin Immunother 2013;9:1:13-25.  |
| 2. | Prochaska JJ. Nicotine Replacement Therapy as a Maintenance Treatment. JAMA 2015;314:718-19. |
| 3. | Raupach T, Hoogsteder PHJ, van Schayck CP. Nicotine Vaccines to Assist with Smoking Cessation Current Status of Research. Drugs 2012;72:e1-e16. |
| 4. | Madiyal A, Ajila V, SubhasBabu G, Hegde S. Knowledge and attitude of South-Indian smokers towards smoking associated health risk. NUJHS 2017;7:24-30. |
| 5. | Tombor I, Vangeli E, West R, Shahab L. Progression towards smoking cessation: Qualitative analysis of successful, unsuccessful, and never quitters, Journal of Substance Use 2017;23:214-22. |
| 6. | Wadgave U, Nagesh L. Nicotine Replcement Therapy: An Overview. Int J Health Sci 2016;10:425-35. |
| 7. | Simon P, Kong G, Cavallo DA, Krishnan-Sarin S. Update of Adolescent Smoking Cessation Interventions: 2009–2014. Curr Addict Rep 2015; 2:15-23. |
| 8. | Green G. Nicotine Replacement Therapy for Smoking Cessation. Am Fam Physician 2015;92:23B-24B. |
| 9. | Lee PN, Fariss MW. A systematic review of possible serious adverse health effects of nicotine replacement therapy. Arch Toxicol 2017;91:1565-94. |
| 10. | Lam DL, Luo SY, Fu KH, Lui MMS, Chan KH, Wistuba II. Nicotinic acetylcholine receptor expression in human airway correlates with lung function. Am J Physiol Lung Cell Mol Physiol 2016;310:L232-L239. |
| 11. | Hukkanen J, Jacob P, Benowitz NL. Metabolism and disposition kinetics of nicotine. Pharmacol Rev 2005;57:79-115. |
| 12. | Rose JE, Mukhin AG, Lokitz SJ, Turkington TG, Herskovic J, Behm FM, et al. Kinetics of brain nicotine accumulation in dependent and nondependent smokers assessed with PET and cigarettes containing 11C-nicotine. Proc Natl Acad Sci U S A 2010;107:5190-5. |
| 13. | Benowitz NL. Nicotine addiction. N Engl J Med 2010;362:2295-303. |
| 14. | A clinical practice guideline for treating tobacco use and dependence: A US Public Health Service report. The Tobacco Use and Dependence Clinical Practice Guideline Panel, Staff, and Consortium Representatives. JAMA 2000;283:3244-54. |
| 15. | Harvey J, Chadi N. Strategies to promote smoking cessation among adolescents. Paediatr Child Health 2016;21:201-4. |
| 16. | Henningfield JE, Fant RV, Buchhalter AR, Stitzer ML. Pharmacotherapy for nicotine dependence. CA Cancer J Clin 2005;55:281-99. |
| 17. | Yildiz D. Nicotine, its metabolism and an overview of its biological effects. Toxicon 2004;43:619-32. |
| 18. | Molyneux A, Králíková E, Himmerová V. ABC of smoking cessation. Nicotine replacement therapy. Cas Lek Cesk 2004;143:781-3. |
| 19. | |
| 20. | Schnoll RA, Goelz PM, Veluz-Wilkins A, Blazekovic S, Powers L, Leone FT, et al. Long-term Nicotine Replacement Therapy: A Randomized Clinical Trial. JAMA Intern Med 2015;175:504-11. |
| 21. | Shiffman S, Rolf CN, Hellebusch SJ, Gorsline J, Gorodetzky CW, Chiang YK, et al. Real-world efficacy of prescription and over-the counter nicotine replacement therapy. Addiction 2002;97:505-16. |
| 22. | Joseph AM, Fu SS, Lindgren B, Rothman AJ, Kodl M, Lando H, et al, Chronic disease management for tobacco dependence: A randomized, controlled trial. Arch Intern Med 2011;171:1894-1900. |
| 23. | Lewis S, Subramanian G, Pandey S, Udupa N. Design, evaluation and pharmacokinetic study of mucoadhesive buccal tablets of nicotine for smoking cessation. Indian J Pharm Sci 2006;68:829-31. [Full text] |
| 24. | Wallstrom M, Nilsson F, Hirsch JM. A randomized, double-blind, placebo-controlled clinical evaluation of a nicotine sublingual tablet in smoking cessation. Addiction 2000;95:1161-71. |
| 25. | Choi JH, Dresler CM, Norton MR, Strahs KR. Pharmacokinetics of a nicotine polacrilex lozenge. Nicotine Tob Res 2003;5:635-44. |
| 26. | Clinical Practice Guideline Treating Tobacco Use and Dependence 2008 Update Panel, Liaisons, and Staff. A clinical practice guideline for treating tobacco use and dependence: 2008 update. A U.S. Public Health Service report. Am J Prev Med 2008;35:158-76. |
| 27. | Seigel MB, Tanwar KL, Wood KS. Electronic cigarettes as a smokingcessation tool: results from an online survey. Am J Prev Med 2011;40:472-5. |
| 28. | Goniewicz ML, Kuma T, GawronM, Knysak J, Kosmider L. Nicotine levels in electronic cigarettes. Nicotine Tob Res 2013;15:158-66. |
| 29. | Palazzolo DL. Electronic cigarettes and vaping: A new challenge in clinical medicine and public health. A literature review. Front Public Health. 2013 Nov 18;1:56. |
| 30. | Jerry JM, Collins GB, Streem D. Ecigarettes: Safe to recommend to patients? Cleve Clin J Med 2015;82:521-6. |
| 31. | Lam C, West A. Are electronic nicotine delivery systems an effective smoking cessation tool? Can J Respir Ther 2015;51:93-8. |
| 32. | Strasser AA, Souprountchouk V, Kaufmann A, Blazekovic S, Leone P, Benowitz NL, et al. Nicotine Replacement, Topography, and Smoking Phenotypes of E-cigarettes. Tob Regul Sci 2016;2:352-62. |
| 33. | Fagerstrom KO, Schneider NG, Lunell E. Effectiveness of nicotine patch and nicotine gum as individual versus combined treatments for tobacco withdrawal symptoms. Psychopharmacology 1993;111:271-277. |
| 34. | Kornitzer M, Boutsen M, Dramaix M, Thijs J, Gustavsson G. Combined use of nicotine patch and gum in smoking cessation: Aplacebo-controlled clinical trial. Prev Med 1995;24:41-7. |
| 35. | Shah SD, Wilken LA, Winkler SR, Lin SJ. Systematic review and meta-analysis of combination therapy for smoking cessation. J Am Pharm Assoc 2008;48:659-65. |
| 36. | Bohadana A, Nilsson F, Rasmussen T, Martinet Y. Nicotine inhaler and nicotine patch as a combination therapy for smoking cessation: A randomized, double-blind, placebo-controlled trial. Arch Intern Med 2000;160:3128-34. |
| 37. | Bullen C, Howe C, Lin RB, Grigg M, Laugesen M, McRobbie H, et al. Precessation nicotine replacement therapy: Pragmatic randomized trial. Addiction 2010;105:1474-83. |
| 38. | Harmey D, Griffin PR, Kenny PJ. Development of novel pharmacotherapeutics for tobacco dependence: Progress and future directions. Nicotine Tob Res 2012;14:1300-18. |
[Table 1], [Table 2]
|
Search Pubmed for