Drugs for Nicotine Dependence

Drugs for nicotine dependence double to triple the chance of stopping tobacco use compared with willpower alone, and work best with behavioural support. The group includes nicotine replacement therapy, varenicline, cytisine and bupropion. Combining medicine with brief advice at every contact is among the most cost-effective interventions in medicine.

Mechanism. Nicotine replacement gives a slower, lower dose of nicotine than smoking, relieving craving and withdrawal. Varenicline and cytisine are partial agonists at the alpha-4 beta-2 nicotinic receptor, easing withdrawal and blunting the reward from smoking. Bupropion inhibits dopamine and noradrenaline reuptake and blocks nicotinic receptors.

Pharmacokinetics. Nicotine has a half-life of about 2 hours, and is cleared by CYP2A6. Varenicline is excreted unchanged by the kidney, half-life 24 hours. Cytisine is cleared by the kidney, half-life 4 to 5 hours. Bupropion is metabolised to active compounds, half-life 20 hours.

Differences. Varenicline is the most effective single agent. Combination nicotine replacement (patch plus a short-acting form) is nearly as effective. Cytisine is cheap and effective, with a short course. Bupropion is less effective than varenicline and has more interactions, but helps those with depression and weight concerns.

• First choice: varenicline, or combination nicotine replacement, or cytisine where available.
• Quit date: set for day 8 with varenicline (flexible between days 8 and 35); on the patch, the first day of use; cytisine day 5.
• Heavy dependence: combination nicotine replacement, starting the highest patch strength.
• Failure: try a different agent, or combine varenicline with a nicotine patch.
• Smokeless tobacco and shisha: nicotine replacement and behavioural support can be used, though evidence is thinner than for cigarettes.
• Hospital and tuberculosis care: offer treatment at the first contact, because stopping improves treatment outcome and survival.
• Relapse: a lapse is not a failure; restart with the same agent or change it.

Special groups. Pregnancy: behavioural support first; if that fails, nicotine replacement (intermittent forms preferred to patches, or patches removed overnight) is safer than smoking; avoid varenicline, cytisine and bupropion unless benefit outweighs risk. Breastfeeding: nicotine replacement is acceptable, taken just after feeding. Adolescents: behavioural support first; nicotine replacement under specialist advice. Older adults: usual doses.

Kidney impairment: varenicline 0.5 mg twice daily maximum with creatinine clearance under 30 mL/min; reduce cytisine. Liver impairment: bupropion 150 mg daily in moderate disease, and avoid in severe disease. Cardiovascular disease: nicotine replacement and varenicline are safe. Psychiatric illness: varenicline and nicotine replacement are safe; monitor mood.

Regional: varenicline and cytisine are not widely stocked; nicotine replacement is costly; smokeless tobacco and shisha are common in some communities.

Adverse effects. Nicotine replacement: skin irritation and sleep disturbance with patches, mouth and throat irritation, hiccups and dyspepsia with gum and lozenges. Varenicline: nausea (about 30%, reduced by taking with food and water), insomnia, abnormal dreams, headache. Cytisine: nausea, dry mouth, headache, sleep disturbance. Bupropion: insomnia, dry mouth, anxiety, headache, rise in blood pressure, and dose-related seizures.

Contraindications. Bupropion: seizure disorder, eating disorders, alcohol or benzodiazepine withdrawal, brain tumour, and monoamine oxidase inhibitors. Nicotine patches: allergy to adhesive. Varenicline: allergy; severe renal impairment needs dose reduction.

Interactions. Stopping smoking removes CYP1A2 induction, so levels of clozapine (rise by up to 50%), olanzapine, theophylline, caffeine, warfarin and flecainide rise within days; reduce doses and check levels. Bupropion inhibits CYP2D6.

Monitoring. Carbon monoxide or self-report at 4 weeks and 12 weeks, mood, sleep, drug levels in people on clozapine, theophylline or warfarin, blood pressure with bupropion.

Referral and escalation. Failure after two different courses, severe mental illness, pregnancy, or suicidal thoughts.