ARTURO G. LERNER, MD Dual Disorders Ward Lev- Hasharon Mental Health Center Netanya, Israel

1. ADDICTION MEDICINE WITH EMPHASIS ON PSYCHOACTIVE SUBSTANCESSchool of Continuing Medical Education Sackler School of Medicine, Tel Aviv UniversityTobacco use disorders: pharmacology, clinical topics, diagnosis and treatment27 April 2010 ARTURO G. LERNER, MD Dual Disorders Ward Lev- Hasharon Mental Health Center Netanya, Israel artura@lev-hasharon.co.il Cellular 050-6267912 Fax: 09-8980313

2. Tobacco use disorders Etymology • The Spanish word "tabaco" is thought to have its origin in the Taino language of the Caribbean. • In Taino, it was said to refer either to a roll of tobacco leaves or to a kind of Y-shaped pipe for sniffing tobacco. • The leaves themselves have being referred to as cohiba. • However, similar words in Spanish and Italian were commonly used from 1410 to define medicinal herbs, originating from the Arabic tabbaq, a word reportedly dating to the 9th century, as the name of various herbs. • The Taínos were pre-Columbian inhabitants of the Bahamas, Greater Antilles and the northern Lesser Antilles.

3. Tobacco use disorders Smokeless tobacco • Snuff is ground or pulverized tobacco, which is generally insufflated or "snuffed" through the nose. It is a type of smokeless tobacco. There are several types, but traditionally it means Dry nasal snuff. In the United States, "snuff" can also refer to dipping tobacco, which is applied to the gums rather than inhaled. • Dipping tobacco is also known as moist snuff or spit tobacco. It is commonly referred to as dip. The act of using it is called dipping. Dip is colloquially or popularly called "chew"; because of this, it is commonly confused with chewing tobacco. It is a version of the Swedish "snus" that was brought to America by Swedish immigrants in the 19th century. Instead of literally chewing on tobacco, a small clump of dip is 'pinched' out of the tin and placed between the lower lip and the gums. The dip rests on the inside lining of the mouth usually for ten to thirty minutes. Nicotine is absorbed by the inferior or superior labial arteries. • Snus is a moist powder tobacco product originated from a variant of dry snuff, in the early 19th century in Sweden, consumed by placing it under the lip for extended periods of time. However the precursor of snus, the dry form of snuff inhaled through the nose, was introduced in Europe much earlier. Snus is a form of snuff that is used in a manner similar to American dipping tobacco, but typically does not result in the need for spitting. Snus is also unique in that it is steam-cured rather than smoke-cured, is not fermented and contains no added sugar. The sale of snus is illegal in the European Union, but due to exemptions, it is still manufactured and consumed primarily in Sweden and Norway, although it is now available in the United States. • Gray N.: “Mixed feelings on snus". Lancet 2005, 366: 966–7

4. Tobacco use disorders Nicotine • Nicotine is named after the tobacco plant Nicotiana tabacum which in turn is named after Jean Nicot de Villemain, French ambassador in Portugal, who sent tobacco and seeds from Brazil to Paris in 1560 and promoted their medicinal use. • Nicotine was first isolated from the tobacco plant in 1828 by German chemists Posselt & Reimann who considered it a poison. • Its chemical empirical formula was described by Melsens in 1843. • Its structure was discovered by Garry Pinner in 1893, and it was first synthesized by A. Pictet and Crepieux in 1904. • Henningfield, JE; Zeller, M. ""Nicotine psychopharmacology", research contributions to United States and global tobacco regulation: A look back and a look forward". Psychopharmacology 2006, 184 (3-4): 286–291

5. Tobacco use disorders • Nicotine is an natural alkaloid found in the nightshade family of plants - Solanaceae that constitutes approximately between 0.6–3.0% of dry weight of tobacco. • Biosynthesis takes place in the roots and accumulation occurring in the leaves. • It functions as an anti-herbivore chemical with particular specificity to insects thus nicotine was widely used as an insecticide in the past, and currently nicotine analogs such as imidacloprid continue to be widely used. • In low concentrations nicotine acts as a stimulant and is the main factor responsible for the dependence of tobacco smoking. • An average cigarette contains approximately about 1 mg of absorbed nicotine.

6. Tobacco use disorders • Nicotine is the psychoactive component of tobacco which affects CNS by acting as an agonist at the nicotinic subtype of acethycholine receptors. • By binding to nicotinic acetylcholine receptors, nicotine increases the levels of several neurotransmitters - acting as a sort of "volume control". It is thought that increased levels of dopamine in the reward circuits of the brain are responsible for the euphoria and relaxation and eventual dependence caused by nicotine consumption. Nicotine has a higher affinity for acetylcholine receptors in the brain. • At toxic doses it can induce contractions and respiratory paralysis. • Tobacco smoke contains the monoamine oxidase inhibitors harman, norharman, anatabine and anabasine (used a insecticide). These compounds significantly decrease MAO activity in smokers. MAO enzymes break down monoaminergic neurotransmitters such as dopamine, norepinephrine, and serotonin. • Chronic nicotine exposure via tobacco smoking up-regulates alpha4beta2 nAChR in cerebellum and brainstem regions. Alpha4beta2 and alpha6beta2 receptors, present in the ventral tegmental area, play a crucial role in mediating the reinforcement effects of nicotine. • Xinan Xiu, Nyssa L. Puskar, Jai A. Pet al. "Nicotine binding to brain receptors requires a strong cation– interaction". Nature 2009, 458: 534-537 • Herraiz T, Chaparro C. "Human monoamine oxidase is inhibited by tobacco smoke: beta-carboline alkaloids act as potent and reversible inhibitors". Biochem. Biophys. Res. Commun. 2005, 326: 378–86 • Fowler JS, Volkow ND, Wang GJ, et al. "Neuropharmacological actions of cigarette smoke: brain monoamine oxidase B (MAO B) inhibition". J Addict Dis 1998, 17: 23–34 • Wüllner U, Gündisch D, Herzog H, et al. "Smoking upregulates alpha4beta2* nicotinic acetylcholine receptors in the human brain". Neurosci. Lett. 2008, 430: 34–7 • Walsh H, Govind AP, Mastro R, et al. "Up-regulation of nicotinic receptors by nicotine varies with receptor subtype". J. Biol. Chem. 2008, 283: 6022–32

7. Tobacco use disorders • Downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external variable. • An example of downregulation is the cellular decrease in the number of receptors to a molecule, such as a hormone or neurotransmitter, which reduces the cell's sensitivity to the molecule. This phenomenon is an example of a locally acting negative feedback mechanism. • Upregulation is the process by which a cell increases the quantity of a cellular component, such as RNA or protein, in response to an external variable. • An example of upregulation is the increment of number of cytochrome P450 enzymes in liver cells which increases the cell's sensitivity.

8. Tobacco use disorders • As nicotine enters the body, it is distributed rapidly through the bloodstream and then can cross the blood-brain barrier. • On average it takes about a few seconds for nicotine to reach the brain when inhaled. • The half life of nicotine in the body is around two hours. • The amount of nicotine absorbed by the body from smoking depends on many factors, including the type of tobacco, whether the smoke is inhaled or filter is used. For chewing or snuffing tobacco, which is held in the mouth between the lip and gum or taken through the nose, the amount released into the body tends to be much greater than smoked tobacco. • Nicotine is metabolized in the liver by cytochrome P450 enzymes (mostly CYP2A6, and also by CYP2B6). • A major metabolite is cotinine. • Other primary metabolites include nicotine N'-oxide, nornicotine, nicotine isomethonium ion, 2-hydroxynicotine and nicotine glucuronide. • Glucuronidation and oxidative metabolism of nicotine to cotinine are both inhibited by menthol, an additive to mentholated cigarettes, thus increasing the half-life of nicotine in vivo. • Benowitz NL, Jacob P, Jones RT et al. "Interindividual variability in the metabolism and cardiovascular effects of nicotine in man". J Pharmacol Exp Ther 1982, 221: 368–72 • Hukkanen J, Jacob P, Benowitz NL., J et al. "Metabolism and Disposition Kinetics of Nicotine". Pharmacol Rev. 2005, 57: 79–115 • Benowitz NL, Herrera B, Jacob P et al. “Mentholated cigarette smoking inhibits nicotine metabolism”. J Pharmacol Exp Ther 2004, 310: 1208–15

9. Tobacco use disorders Acetylcholine receptors • Acetylcholine receptors can be divided into muscarinic and nicotinic types. • Muscarinic receptors (mAChRs) can be activated by acetylcholine and muscarine. • Nicotinic receptors can be activated by acetylcholine and nicotine. • Nicotinic acetylcholine receptors (nAChRs) are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction . They are directly linked to an ion channel and do not make use of a second messenger. • Nicotinic receptors share similarities with GABAA complex and the 5HT3 type SE receptors. • Nicotinic receptors are broadly classified into two subtypes based on their primary sites of expression: muscle type and neuronal type. • In the muscle type, found at the neuromuscular junction, receptors are either the embryonic form (less specialized) , composed of α1, β1, δ, and γ subunits or the adult form composed of α1, β1, δ, and ε subunits. • The neuronal subtypes are various combinations of twelve different nicotinic receptor subunits: α2 through α10 and β2 through β4. • Xinan Xiu, Nyssa L. Puskar, Jai A. Pet al. "Nicotine binding to brain receptors requires a strong cation– interaction". Nature 2009, 458: 534-537 • Herraiz T, Chaparro C. "Human monoamine oxidase is inhibited by tobacco smoke: beta-carboline alkaloids act as potent and reversible inhibitors". Biochem. Biophys. Res. Commun. 2005, 326: 378–86 • Fowler JS, Volkow ND, Wang GJ, et al. "Neuropharmacological actions of cigarette smoke: brain monoamine oxidase B (MAO B) inhibition". J Addict Dis 1998, 17: 23–34 • Wüllner U, Gündisch D, Herzog H, et al. "Smoking upregulates alpha4beta2* nicotinic acetylcholine receptors in the human brain". Neurosci. Lett. 2008, 430: 34–7 • Walsh H, Govind AP, Mastro R, et al. "Up-regulation of nicotinic receptors by nicotine varies with receptor subtype". J. Biol. Chem. 2008, 283: 6022–32

10. Tobacco use disorders Tobacco smoking • Nicotine's mood-altering effects can be both stimulation and relaxation. • First causing a release of glucose from the liver and adrenaline from the adrenal medulla, it causes stimulation. Users report feelings of relaxation, sharpness, calmness, and alertness. • By reducing the appetite and raising the metabolism, some smokers may lose weight as a consequence. • When a cigarette is smoked, nicotine-rich blood passes from the lungs to the brain within a few seconds and immediately stimulates the release of many chemical messengers including acetylcholine, norepinephrine, epinephrine, vasopressin, arginine (Arginine is the immediate precursor of nitrous oxide and urea; is necessary for the synthesis of creatine), dopamine, and beta-endorphin. • This release of neurotransmitters and hormones is responsible for most of nicotine's effects. Nicotine appears to enhance concentration, memory and alertness due to the increases of acetylcholine and norepinephrine. • Arousal is increased by the increase of norepinephrine. • Pain is reduced by the increases of acetylcholine and beta-endorphin. • Anxiety is reduced by the elevation of beta-endorphin. • Nicotine also extends the duration of positive effects of dopamine and increases sensitivity in brain reward systems. • Kenny PJ, Markou A "Nicotine self-administration acutely activates brain reward systems and induces a long-lasting increase in reward sensitivity". Neuropsychopharmacology 2006, 31: 1203–11

11. Tobacco use disorders Tobacco smoking • Smokers who wish to achieve a stimulating effect take short quick puffs, which produce a low level of blood nicotine. This stimulates nerve transmission. • Smokers who wish to relax they take deep puffs, which produce a high level of blood nicotine, which depresses the passage of nerve impulses, producing a mild sedative effect. • At low doses, nicotine potently enhances the actions of norepinephrine and dopamine in the brain, causing a drug effect typical of those of psychostimulants. • At higher doses, nicotine enhances the effect of serotonin and opiate activity, producing a calming, pain-killing effect. • Nicotine is unique in comparison to most drugs, as its profile changes from stimulant to sedative/pain killer in increasing dosages and use. Alcohol behaves similarly. • Villégier AS, Blanc G, Glowinski J, Tassin JP. "Transient behavioral sensitization to nicotine becomes long-lasting with monoamine oxidases inhibitors". Pharmacol. Biochem. Behav. 2003, 76 (2): 267–74

12. Tobacco use disorders Diseases associated to Tobacco Use • Tobacco use is associated to the genesis of a large number of diseases and disorders. • The carcinogenic properties of nicotine in standalone form, separate from tobacco smoke, have not been evaluated • The currently available literature indicates that nicotine, on its own, does not promote the development of cancer in healthy tissue and has no mutagenic properties. • However, nicotine and the increased cholinergic activity it causes have been shown to impede apoptosis, which is one of the methods by which the body destroys unwanted cells (programmed cell death). • Since apoptosis helps to remove mutated or damaged cells that may eventually become cancerous, the inhibitory actions of nicotine may create a more favorable environment for cancer to develop, though this also remains to be proven. • Lung damage • Heart damage • Blood vessel damage • Lung cancer • Emphysema • Chronic bronchitis • Involuntary exposure to secondhand smoke

13. Tobacco use disorders ICD classification uses the term Tobacco and not Nicotine. DSM IV-TR does not have criteria for Nicotine intoxication and abuse. Diagnostic Criteria for Nicotine Withdrawal: A. Daily use of nicotine for at least several weeks. B. Abrupt cessation of nicotine use, reduction in the amount of nicotine used, followed within 24 hours by four (or more) of the following symptoms: • Dysphoric or depressed mood • Insomnia • Irritability, frustration or anger • Anxiety • Difficulty concentrating • Restlessness • Decreased heart rate • Increased appetite or weight gain C. The symptoms in criterion B cause clinically significant distress or impairment in social, occupational or other important areas of functioning • Harmful use

14. Tobacco use disorders Low nicotine cigarettes • Tobacco company executives who market their cigarettes in Israel as "lite," "low tar," "mild," or "low nicotine" could face a prison sentence of one to two years. • This is the prescribed but little used punishment for violation of the 1981 Consumer Protection Law, which is the basis for a criminal investigation just launched by the ministry of commerce and industry against cigarette manufacturers and importers. They are suspected of misleading the public into believing that this form of tobacco is "safer" than ordinary cigarettes. • The investigation was initiated after the filing of a lawsuit in the Jerusalem district court last June by lawyers for Clalit Health Services, Israel's largest public health fund. They asked for an injunction to prevent cigarette manufacturers and importers from using the terms "light," "mild," "low tar," and "low nicotine" to describe and market their products. • The health fund argued that these terms were misleading because tobacco companies themselves had in several forums admitted that cigarettes with less tar or nicotine were no less dangerous to health. The court has not yet ruled in the case, but the ministry was pressed into taking action on its own by the lawyers' request for an injunction and efforts by the Israel Consumer Council. • As many as half of all cigarette sales in Israel are of "lite" or similarly "reduced" brands. Marlboro Lights, made by Philip Morris, is the most popular brand sold in the Israel Defence Forces' kiosks frequented by soldiers. • The European parliament recently recommended to its 15 member governments that tobacco companies be barred from using such terms on the grounds that they falsely suggest lowertoxicity, but its recommendations are not due to come into effect until 2003. • Judy Siegel-Itzkovich: Israel investigates tobacco firms for misleading the public. BMJ. 2001; 323: 956.

15. Tobacco use disorders Low nicotine cigarettes • Brazil was the first country in the world to put such a prohibition into force, followed by Canada. Israel could be the third to do so, said Amos Hausner and Lipa Meir, lawyers for Clalit Health Services. • The lawyers are also seeking nearly £1.3bn ($2bn) on behalf of the health fund in compensation for its huge expenses in treating smokers who become ill. Mr Hausner said that this was the first time anywhere in the world that a criminal investigation had been launched against tobacco companies suspected of defrauding the public by using misleading advertising terms. • Foreign brands being sold in Israel include L&M Lites and brands of the Brown & Williamson and British American Tobacco companies, and the Israeli tobacco company Dubek produces Time Lite and Golf. • The lawyers for Clalit Health Services presented documents to the court in which tobacco companies had conceded that lower tar and lower nicotine cigarettes were not "safer" than ordinary cigarettes and that cigarettes that are "mild" emitted higher concentrations of toxic substances than those that are not. A Canadian survey of smokers recently showed that most of them bought mild cigarettes because they thought they posed less of a health danger. • Judy Siegel-Itzkovich: Israel investigates tobacco firms for misleading the public. BMJ. 2001; 323: 956.

16. Tobacco use disorders Low nicotine cigarettes • Dr Yitzhak Peterburg, director general of Clalit Health Services, maintained that many smokers were "tricked" into thinking that if they smoked mild or lite cigarettes, they enjoyed "health benefits." But that was not true, he said, and the companies had used these false messages to dupe the public. Children and teenagers were most easily lured into smoking by these brands, he said, adding that he hoped that an end to misleading advertising and marketing would reduce sales and damage from smoking. • A statement by David Kessler, a former commissioner of the US Food and Drug Administration and author of a recent book on the tobacco industry called A Question of Intent , was presented to the district court. He wrote that smokers of mild or lite cigarettes did not realise these caused just as much nicotine to be absorbed by their body as other cigarettes. • Asked to comment, a spokeswoman for Dubek, Hava Barak, claimed that the tobacco company had "never used health claims for using its ‘lite' brands" and that it regarded the term "solely as a definition of the taste of the cigarette." • The Eliachar tobacco importing company commented that terms such as "ultra-light" and "full flavor" were mere "descriptors and facilitate consumers' ability to distinguish among different product offerings." • Judy Siegel-Itzkovich: Israel investigates tobacco firms for misleading the public. BMJ. 2001; 323: 956.

17. Tobacco use disorders Components of cigarettes • Brand: Camel Light (example) • Tar: 8 mg • Nicotine: 0.67 mg • Weight: 0.928 g • CO: 10.2 mg • Nicotine - Tar Ratio: 0.084 • Mendenhall, William, and Sincich, Terry (1992), Statistics for Engineering and the Sciences (3rd ed.),New York: Dellen Publishing Co. • Erowid

18. Tobacco use disorders Nicotine testing • Urine Testing Inexpensive test strips are available that detect cotinine, a nicotine metabolite, in urine by immunoassay. These tests are not very sensitive (cutoff around 200 ng/ml) and they can only detect cotinine for about 2-5 days. • Hair Testing Nicotine and cotinine can be detected in hair with a detection cutoff around 2 ng/ml (nicotine). Hair tests have a much longer detection window than fluid tests. • Saliva Testing Cotinine can be detected by quick, inexpensive saliva tests. Some saliva tests are extremely sensitive, detecting cotinine at concentrations as low as 1 ng/ml. Nicotine and cotinine can be detected in saliva with more sensitive and expensive procedures, such as HPLC –High performance liquid chromatography. The detection window for these procedures is around 7-10 days. • Blood Testing Nicotine and cotinine are detectable in the blood with laboratory testing, for about 7-10 days.

19. Tobacco use disorders Quitting Common therapies • Self quit • Self help books • Physician advice • Over the counter medications • Medication plus advice • Specific medication plus advice • Behavior therapy • Medication plus group therapy

20. Tobacco use disorders Smoking cessation Pharmacological treatment • Abrupt: “cold turkey” or abrupt cessation of all the intake of nicotine. • Gradual: gradual reduction of the number of smoked cigarettes. Switch to cigarettes with lower percentage of nicotine. • Research suggests that gradual reductions may lead to levels below the "minimum daily amounts" required to maintain an addiction, which could then facilitate complete cessation of smoking. • Doran CM, Valenti L, Robinson M, Britt H, Mattick RP. Smoking status of Australian general practice patients and their attempts to quit. Addict Behav. 2006, 31:758-66

21. Tobacco use disorders Smoking cessation Pharmacological treatment First line pharmacological treatments: • Nicotine replacement therapy (NRT): patch, gum, inhaler, lozenge, spray and sublingual tablet • NDRIs: bupropion (Zyban) • Nicotine receptor agonist: varenicline (Champix) Second line pharmacological treatments: • Clonidine (Normopressan 0.25 mg, Clonnirit 75 mcg) ( 1 Normopressan = 6 Clonnirit) • Nortriptyline (Nortylin 10 and 25 mg) Third line pharmacological treatmenst - augmentation strategies: • NRT + bupropion • NRT + nortryptilin • NRT + antidepressants • Nides M.: Update on pharmacologic options for smoking cessation treatment. Am J Med. 2008,121:S1 20-31. • Berlin I.: Therapeutic strategies to optimize the efficacy of nicotine replacement therapies. COPD 2009, 64:272-6. • Melero A, Garrigues TM, Alós M: Nortriptyline for smoking cessation: release and human skin diffusion from patch. Int J Pharm. 2009, 13;378:101-7.

22. Tobacco use disorders Smoking cessation Pharmacological treatment Nicotine replacement therapy (NRT) • Nicotine replacement therapy (NRT) is the use of various forms of nicotine delivery methods intended to replace nicotine obtained from smoking or other tobacco usage. Types • Nicotine patch – Nicotinell TTS, Niquitin CQ (nicotine 7, 14 and 21 mg) • Nicotine gum – Nicorette- Nicotinell (nicotine 2 and 4 mg) • Nicotine inhaler – Nicorette inhaler (nicotine 10 mg) • Nicotine lozenge – Nicotinell (nicotine 1 mg) • Nicotine spray • Nicotine sublingual tablet • Transdermal nicotine patches deliver doses of the addictive chemical nicotine, thus reducing the unpleasant effects of nicotine withdrawal. These patches can give smaller and smaller doses of nicotine, slowly reducing dependence upon nicotine and thus tobacco. This method becomes most effective when combined with other medication and psychological support.

23. Tobacco use disorders Bupropion • Bupropion – Wellbutrin (PPC 2hours), WellbutrinSR (PPC 3 hours), WellbutrinXR (PPC 5 hours), Zyban), previously known as amfebutamone, is an atypical antidepressant (NDRI) and smoking cessation aid. It acts as a NE and DA reuptake inhibitor, as well as α3β4-nicotinic non competitive receptor antagonist. Bupropion belongs to the chemical class of aminoketones and is similar in structure to stimulants cathinone and diethylpropion, and to phenethylamines in general. • Bupropion lowers seizure threshold and its potential to cause seizures was widely publicized. However, at the recommended dose the risk of seizures is comparable to that observed for other antidepressants. • Bupropion is an effective antidepressant on its own but it is particularly popular as an add-on medication in the cases of incomplete response to the first-line selective serotonin reuptake inhibitor (SSRI) antidepressant. • Bupropion does not cause weight gain or sexual dysfunction. • Slemmer J E, Martin R M, Damaj M I (2000). "Bupropion is a Nicotinic Antagonist". J Pharmacol Exp Ther295 (1): 321–327. . • Fryer J D, Lukas R J (1999). "Noncompetitive functional inhibition at diverse, human nicotinic acetylcholine receptor subtypes by bupropion, phencyclidine, and ibogaine". J Pharmacol Exp Ther288 (6): 88–92. • PPC: peak plasma concentration

24. Tobacco use disorders Bupropion Smoking cessation • Bupropion reduces the severity of nicotine cravings and withdrawal symptoms. • Bupropion treatment course lasts for seven to twelve weeks, with the patient halting tobacco use about ten days into the course. • The efficacy of bupropion is similar to that of nicotine replacement therapy. • The combination of bupropion and nicotine appears not to further increase the cessation rate. • Bupropion slows weight gain that often occurs in the first weeks after smoke quitting. • Tonnesen P, Tonstad S, Hjalmarson A, Lebargy F, Van Spiegel P I, Hider A, Sweet R, Townsend J (2003). "A multicentre, randomized, double-blind, placebo-controlled, 1-year study of bupropion SR for smoking cessation". J Intern Med254 (2): 184–192. • Wu P, Wilson K, Dimoulas P, Mills E J (2006). "Effectiveness of smoking cessation therapies: a systematic review and meta-analysis". BMC Public Health6: 300–315.

25. Tobacco use disorders Bupropion Method of administration • Zyban should be used in accordance with smoking cessation guidelines. • Prescribers should assess the patient's motivation to quit. • Smoking cessation therapies are more likely to succeed in those patients whom are motivated to quit and have motivational support. • Zyban tablets should be swallowed whole. The tablets should not be crushed or chewed as this may lead to an increased risk of adverse effects including seizures. • Zyban can be taken with or without food. • Patients should be treated for 7-9 weeks. • Although discontinuation reactions are not expected with Zyban, a tapering-off period may be considered. • If at seven weeks no effect is seen, treatment should be discontinued.

26. Tobacco use disorders Bupropion Common side effects • Headache • Insomnia • Dry mouth • Weight loss • Tremor • Nausea • Constipation • Hypertension • Seizures – incidence of 0.05 percent at 300 mg SR

27. Tobacco use disorders Varenicline • Varenicline (Champix 0.5 and 1 mg ) is a nicotinic receptor partial agonist. In this respect, it is different from the nicotinic antagonist (bupropion), and nicotine replacement therapies (NRTs) like nicotine patches and gum. • Asa partial agonist, it both reduces cravings for and decreases the pleasurable effects of cigarettes and other tobacco products, and through these mechanisms it can assist some patients to quit smoking. • Varenicline is an alternative to NRTs and agonist medication. • The FDA has approved its use for twelve weeks. If smoking cessation has been achieved it may be continued for another twelve weeks. • Jorenby D E, Hays J T, Rigotti N A, Azoulay S, Watsky E J, Williams K E, Billing C B, Gong J, Reeves K R (2006). "Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial". JAMA296 (1): 56–63. • Jorenby D E, Hays J T, Rigotti N A, Azoulay S, Watsky E J, Williams K E, Billing C B, Gong J, Reeves K R (2006). "Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial". JAMA296 (1): 56–63

28. Tobacco use disorders Varenicline Mechanism of action • Varenicline is a partial agonist of the α4β2 subtype of the nicotinic acetylcholine receptor. • It also acts on α3β4 and weakly on α3β2 and α6-containing receptors. • A full agonism was displayed on α7-receptors. • Acting as an agonist varenicline binds to, and partially stimulates, the receptor without creating a full nicotine effect on the release of dopamine. • Mihalak KB, Carroll FI, Luetje CW (2006). "Varenicline is a partial agonist at alpha4beta2 and a full agonist at alpha7 neuronal nicotinic receptors". Mol. Pharmacol. 70 (3): 801–5.

29. Tobacco use disorders Varenicline Method of administration • The patient should set a date to stop smoking. CHAMPIX dosing should start 1-2 weeks before this date. • Patients who cannot tolerate adverse effects of CHAMPIX may have the dose lowered temporarily or permanently to 0.5 mg twice daily. • CHAMPIX tablets should be swallowed whole with water. CHAMPIX can be taken with or without food. • Patients should be treated with CHAMPIX for 12 weeks. • For patients who have successfully stopped smoking at the end of 12 weeks, an additional course of 12 weeks treatment with CHAMPIX at 1 mg twice daily may be considered . • No data are available on the efficacy of an additional 12 weeks course of treatment for patients who do not succeed in stopping smoking during initial therapy or who relapse after treatment. • In smoking cessation therapy, risk for relapse to smoking is elevated • in the period immediately following the end of treatment. In patients with a high risk of relapse, dose tapering may be considered .

30. Tobacco use disorders Varenicline Side effects • Nausea • Headache, difficulty sleeping, and abnormal dreams • Change in taste, vomiting, abdominal pain, flatulence and constipation • Suicidal ideation and occasional suicidal behavior • Erratic behavior and mood swings • "Early Communication About an Ongoing Safety Review: Varenicline . United States Food and Drug Administration. November 20 2007. • McClure JB, Swan GE, Jack L, et al. (May 2009). "Mood, side-effects and smoking outcomes among persons with and without probable lifetime depression taking varenicline". J Gen Intern Med24 (5): 563–9.

31. Tobacco use disorders Other references • Kaplan & Sadock’s Synopsis of Psychiatry (2007) • DSM IV TR (2000) • Textbook of Substance Abuse Treatment • Wikipedia articles • Erowid articles • NIDA