26. The Reward Pathway Dopamine surge in the nucleus accumbens is thought to produce the same positive motivational state associated with food and sex
27. The Reward Pathway While all highly addictive drugs activate the mesolimbic pathway, nicotine is a particularly reinforcing drug because it is inhaled and nicotine levels in the brain rise very rapidly (within 10 secs), producing a more powerful effect than drugs taken orally
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69. Champix ® (Varenicline): A Highly Selective 4 2 Receptor Partial Agonist 1. Coe JW et al. Presented at the 11th Annual Meeting and 7th European Conference of the Society for Research on Nicotine and Tobacco. 2005. Prague, Czech Republic. 2. Picciotto MR et al. Nicotine Tob Res. 1999; Suppl 2:S121-S125. Binding of nicotine at the 4 2 nicotinic receptor in the VTA is believed to cause release of dopamine at the nAcc Champix is an 4 2 nicotinic receptor partial agonist, a compound with dual agonist and antagonist activities. This is believed to result in both a lesser amount of dopamine release from the VTA at the nAcc as well as the prevention of nicotine binding at the 4 2 receptors. Nicotine Champix
70. Varenicline: 4 2 nAChR Partial Agonists 4 2 nAChR Dual action of a partial agonist Agonist Response 100% Smoking No Partial Ag No Smoking Partial Ag Smoking + Partial Ag Antagonist Partial Agonist Nicotine Part Ag Part ag Nicotine 50% Potential to block reinforcing effects when smoking 50% Potential to relieve craving and withdrawal when quitting
78. Comparative Daily Costs of Pharmacotherapy Cost per day, in U.S. dollars $6.07 $5.81 $5.73 $5.26 $3.91 $3.67 $4.22 $4.26
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80. Smoking Cessation: A Very Powerful Intervention… Critchley JA, Capewell S. JAMA ;2003;290:86-97 Intervention Reduction in Mortality Smoking Cessation 36% Statin Therapy 29% Beta-Blockers 23% ACE Inhibitors 23% Aspirin 15%
81. Effects of Clinician Interventions Estimated abstinence at 5+ months 1.0 1.1 (0.9,1.3) 1.7 (1.3,2.1) 2.2 (1.5,3.2) n = 29 studies Type of clinician Fiore et al. Treating Tobacco Use and Dependence. Clinical Practice Guideline. USDHHS, PHS, 2000. Compared to smokers who receive no assistance from a clinician, smokers who receive such assistance are 1.7 – 2.2 times as likely to quit successfully for 5 or more months.
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Editor's Notes
Notes: GlaxoSmithKline offers an integrated approach to successful quitting: endorsement and promotion of healthcare professional involvement – imparting knowledge, confidence, motivation and commitment to smokers who want to quit advanced pharmacotherapies help smokers to combat cravings behavioral support plans help to maintain motivation and ensure the individual is well informed on all aspects of smoking cessation, providing the best opportunity for success.
Expressing empathy – reflective listening ala Rogers, ambivalence is the normal human condition
Key Point Varenicline, the active ingredient in Champix (as the tartrate salt), is a partial agonist selective for α4β2 nicotinic acetylcholine receptor subtypes. Background Varenicline, the active ingredient in Champix (as the tartrate salt), is a partial agonist with high selectivity and affinity for α4β2 nicotinic acetylcholine receptor subtypes. Varenicline tartrate is a white to off-white to slightly yellow powder that is highly soluble in water, with a molecular formula of C 13 H 13 N 3 • C 4 H 6 O 6 . Reference 1. Chantix package insert. Pfizer Labs, a division of Pfizer Inc., New York, NY, USA PI/p. 5/¶1,2
Key Point Champix ™ (varenicline) was deliberately designed for the 4 2 receptor, as an 4 2 nicotinic receptor partial agonist (with dual agonist and antagonist properties) and physically prevents nicotine from binding as an aid in smoking cessation. Background The initial view of the mesolimbic system identifies the VTA where the 4 2 receptors predominate, as well as the nAcc. The release of dopamine at the nAcc from the axons of the dopamine cells of the VTA is believed to produce a reward response. When nicotine binds at the 4 2 nicotinic receptor in the VTA, it is believed to cause release of dopamine at the nAcc. Champix ™ (varenicline) was deliberately designed for the 4 2 receptor, as an 4 2 nicotinic receptor partial agonist (with dual agonist and antagonist properties) and physically prevents nicotine from binding and releases intrinsically less dopamine at the nAcc. References Coe JW, Brooks PR, Wirtz MC, et al. Varenicline (CP-526, 555): A novel, potent, and selective nicotinic receptor partial agonist for the treatment of smoking cessation: Rationale, discovery, and mode of action. Presented at the 11th Annual Meeting and 7th European Conference of the Society for Research on Nicotine and Tobacco, March 20–23, 2005, Prague, Czech Republic. Picciotto MR, Zoli M, Changeux J. Use of knock-out mice to determine the molecular basis for the actions of nicotine. Nicotine Tob Res. 1999; Suppl 2:S121-S125.
With this compound you can see that nicotine binds to alpha-4 beta-2 nicotinic receptors in the VTA of the brain causing an agonist or 100% response. In theory Chantix will, by being a partial agonist, bind and give a partial agonist response, which we refer to as 40% in terms of dopamine release. By occupying the receptor, you can see that nicotine is unable to attach to the receptor once Chantix is on board. Therefore by smoking you receive no additional reward, but you don’t also have the low levels of dopamine that would lead to a relapse to smoking. These were the intended and hopefully achievable objectives of the program at the outset in 1993. A partial agonist would be a novel objective for Pfizer, and the industry.
Key Point Varenicline is indicated for smoking cessation in adults. Background Varenicline is indicated for smoking cessation in adults. When prescribing varenicline, physicians also should provide patients with advice and support concerning their attempt at quitting smoking, as smoking cessation therapies appear to be more likely to be successful in conjunction with behavioral interventions. Patients must choose a date to quit smoking and initiate varenicline treatment 1 – 2 weeks before this date. Varenicline should be taken with a full glass of water, with or without food, with titration according to the following schedule: an initial dose of one 0.5 mg tablet once daily for the first 3 days, then one 0.5 mg taken in the morning and one 0.5 mg tablet taken in the evening for the next four days up to day 7. After the first 7 days, the dose should be increased to one 1.0 mg tablet in the morning and one 1.0 mg tablet in the evening. Patients who cannot tolerate varenicline may have the dose lowered temporarily or permanently to 0.5 mg BID. Reference 1. Champix Summary of Product Characteristics. Pfizer Ltd, Sandwich, UK. 2006. Champix Summary of Product /p 2/¶6,7,9-11;Table Champix Summary of Product /p 2/¶6,7,9-11;Table
Key Point Among varenicline’s pharmacokinetic properties, clinically relevant features include: maximum plasma concentrations within 3 – 4 hours after administration, steady-state conditions within 4 days, bioavailability unaffected by food or time-of-day dosing, varenicline undergoes minimal metabolism, its elimination half-life is approximately 24 hours, and it exhibits linear kinetics. PI/p. 6/¶2,3,4; p. 7/¶6 PI/p. 6/¶2,3,4; p. 7/¶6
Key Point The percentage of participants who discontinued treatment due to AEs receiving varenicline treatment was 11.4% vs 9.7% receiving placebo. More study participants who received varenicline treatment experienced nausea (28.6%) compared with those who received placebo. Background Approximately 4000 individuals were exposed to varenicline during clinical trials for up to 1 year (average 84 days). In placebo-controlled trials, the treatment discontinuation rate due to AEs was comparable between treatment groups: 11.4% in patients who received varenicline 1.0 mg twice daily compared with 9.7% in those who received placebo. Reference 1. Varenicline Summary of Product Characteristics. Pfizer Ltd, Sandwich, UK. 2006. Varenicline Summary of Product doc/p.5/¶3,4,5 Varenicline Summary of Product doc/p.5/¶3,4,5 Varenicline Summary of Product doc/p.5 and 6 Table
Key Point Varenicline has no meaningful drug interactions. Background Hypersensitivity to the active substance or to any of the excipients is the only contraindication to the use of varenicline. Special warnings and precautions include the independent effects of smoking cessation, with or without varenicline therapy. These effects involve the physiological changes resulting from smoking cessation, which may alter the pharmacokinetics or pharmacodynamics of some medicinal products and necessitate dosage adjustment. Further, smoking cessation has been associated with exacerbation of underlying psychiatric illness, so care should be taken with patients with a history of psychiatric illness. Discontinuation of varenicline was associated with an increased in irritability, urge to smoke, depression, and/or insomnia in up to 3% of patients. Patients should therefore be informed accordingly, and the need for dose tapering should be considered by the prescriber. Drug interaction studies have included combinations of varenicline and metformin, cimetidine, digoxin, and warfarin, and have identified no clinically meaningful pharmacokinetic drug–drug interactions. In addition, varenicline has been evaluated with concurrent use with other therapies for smoking cessation. Varenicline did not alter the steady-state pharmacokinetics of bupropion, though there was a statistically significant increase in average systolic blood pressure (mean 2.6 mmHg) when varenicline and transdermal NRT were coadministered for 12 days. The incidence of nausea, headache, vomiting, dizziness, dyspepsia, and fatigue was greater for the combination of varenicline and NRT than for NRT monotherapy. Reference 1. Champix Summary of Product Characteristics. Pfizer Ltd, Sandwich, UK. 2006 . Champix Summary of Product /p 3/ ¶8-12; p 4/¶1,10,11 Champix Summary of Product /p 3/ ¶8-12; p 4/¶1,10,11
Key Point As data are currently inadequate, varenicline should not be used during pregnancy. Benefits to both child and woman should be taken into account when deciding whether a patient should breastfeed or take varenicline. Potentially hazardous activities should be avoided until it is know whether use of varenicline will affect the ability to perform these activities. Background There are no adequate data from the use of varenicline in pregnant women, but studies in animals have shown reproductive toxicity. Although the potential risk for humans is unknown, varenicline should not be used during pregnancy. Similarly, animal studies suggest that varenicline is excreted in breast milk, but it is unknown whether this occurs in humans. The decision to discontinue breastfeeding or discontinue varenicline therapy should therefore take into account the benefits of breastfeeding to the child and varenicline therapy to the woman. Varenicline may have minor or moderate influence on the ability to drive and use machines because dizziness and somnolence may occur. Patients are advised not to engage in potentially hazardous activities until it is known whether their ability to perform these activities is affected while taking varenicline. Reference 1. Champix Summary of Product Characteristics. Pfizer Ltd, Sandwich, UK. 2006. Champix Summary of Product /p 4/ ¶14-15; p 5/¶ 1 Champix Summary of Product /p 4/ ¶14-15; p 5/¶ 1
