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Mechanistic Deep Dive
Nicotine Addiction Pathways
- Mesolimbic dopamine system
- α4β2 nAChR most relevant
- Receptor up-regulation with chronic use
- Genetic factors (CYP2A6 metabolism)
Varenicline Mechanism
- Partial agonist at α4β2
- Both blocks nicotine + provides partial activation
- Reduces cravings + reinforces non-smoking
- Newer drug development continues
CYP2A6 + Smoking Behavior
- Genetic polymorphism
- Slow metabolizers smoke less
- Fast metabolizers harder to quit
- Pharmacogenetics emerging
Recent Trials & Updates
EAGLES (2016)
- Varenicline + bupropion vs NRT vs placebo
- 8,144 participants
- Varenicline most effective
- No excess neuropsychiatric in mental health subgroup
- Practice-changing (FDA boxed warning removed)
Combination NRT Trials
- Patch + short-acting more effective
- Practice-changing
E-Cigarette RCTs
- Hajek 2019 NEJM: e-cigarette > NRT
- Cochrane 2024: e-cigarettes effective for some
- Heterogeneous evidence
Cytisine FDA Update 2024
- Approval pending
- Cheaper alternative
Smoking Cessation in Lung Cancer
- CISL trial
- Significantly improves outcomes
- Cancer-specific interventions
Long COVID + Smoking
- Greater long COVID risk
- Cessation may help recovery
High-Yield Specialist Points
Varenicline Practical Use
- Start 1 week before quit date OR
- Reduce-then-quit model (start while smoking, reduce gradually)
- 12 weeks initial; can extend to 24
- Monitor for nausea (take with food)
NRT Selection
- Heavy smoker: high-dose patch (21 mg)
- Light smoker: lower-dose patch
- Add short-acting for cravings
- Inhaler / nasal spray for behavioral substitute
Bupropion Caveats
- Seizure risk increases at > 450 mg/day
- Avoid in bulimia/anorexia
- Drug interactions (CYP2B6)
Smoking Cessation + Diabetes
- Blood sugar may worsen short-term
- Pharmacotherapy still recommended
- Long-term diabetes control improves
Mental Health + Smoking
- Schizophrenia, bipolar, depression
- Heavy smokers
- More withdrawal symptoms
- Combination therapy + tailored support
- EAGLES: varenicline safe in mental health
Polysubstance Use
- Coexisting alcohol, opioid use
- Address concurrently
- Increases withdrawal complexity
Smoking Cessation Cost-Effectiveness
- Most cost-effective health intervention
- $1500-3500 per QALY
- Far below standard thresholds
Smokeless Tobacco
- Snus, chewing tobacco
- Health risks present (oral cancer, etc.)
- Less than combustible
- Cessation similar approach
Genetic Testing for Smoking Cessation
- Pharmacogenetics emerging
- CYP2A6 markers
- Personalized medicine future
Marijuana + Tobacco
- Coexisting use common
- Coexisting addiction
- Address both
Heated Tobacco Products (HTPs)
- IQOS, glo, others
- Lower toxin levels than combustible
- Regulation evolving
- Cessation tool? Controversial
Pearls
- Tobacco = #1 preventable cause of death
- 5Aâs: Ask, Advise, Assess, Assist, Arrange
- 5Râs: Relevance, Risks, Rewards, Roadblocks, Repetition
- Varenicline most effective single agent
- Combination NRT > single NRT
- EAGLES: removed FDA boxed warning for varenicline neuropsychiatric
- Cytisine alternative; FDA pending
- Pharmacotherapy + behavioral = best outcomes
- Cancer survivors: quitting improves survival 30-50%
- Pregnancy: NRT considered (less than smoking risk)
- EVALI: vitamin E acetate from THC vapes
- Lung cancer screening + cessation synergistic