Is bupropion (Wellbutrin/Zyban) appropriate as a first‑line medication for smoking cessation, and what are the recommended dosing, contraindications, side effects, and alternative therapies?

Bupropion (Wellbutrin/Zyban) for Smoking Cessation

Bupropion SR 150 mg twice daily (300 mg/day total) is an appropriate and effective first-line medication for smoking cessation, increasing 12-month quit rates by approximately 9-10 percentage points above placebo when combined with behavioral support. 1, 2

Recommended Dosing Protocol

Start bupropion 1-2 weeks before your patient's target quit date to establish therapeutic drug levels before the cessation attempt. 1, 3, 2

Standard Titration Schedule:

• Days 1-3: 150 mg orally once daily 1
• Day 4 through 7-12 weeks: 150 mg orally twice daily if tolerated 1
• Maximum dose: 300 mg per day for smoking cessation (do not exceed to maintain seizure risk at 0.1%) 1, 2

Treatment Duration:

• Continue for 7-12 weeks after the quit date 1, 3, 2
• Assess efficacy formally after this 7-12 week period—if no significant progress toward abstinence, reassess the treatment plan 2
• Longer treatment duration may help prevent relapse in patients who successfully quit 1

Efficacy and Clinical Outcomes

Bupropion demonstrates robust efficacy across multiple high-quality trials:

• Quit rates improve from approximately 11% with placebo to 19-21% with bupropion at 12 months 2, 4
• The effect is independent of bupropion's antidepressant properties, making it effective even in patients without depression 1, 2
• Bupropion relieves nicotine withdrawal symptoms and attenuates post-cessation weight gain (1.5-1.7 kg versus 2.1 kg with placebo at 7 weeks) 3, 5
• Patients with comorbid depression may derive particular benefit, as bupropion addresses both conditions simultaneously 1, 3

Absolute Contraindications

Screen carefully for these contraindications before prescribing:

• Any seizure disorder or history of seizures (bupropion lowers seizure threshold) 1, 2, 6
• Brain metastases or stroke (increased seizure risk) 1
• Eating disorders (bulimia or anorexia nervosa—increased seizure risk) 3, 2
• Current or recent MAOI use (within 14 days—risk of hypertensive reactions) 1, 2
• Severe hepatic cirrhosis 2, 7
• Abrupt discontinuation of alcohol, benzodiazepines, or antiepileptic drugs (precipitates seizures) 3, 2
• Hypersensitivity to bupropion or its metabolites 7
• Concurrent tamoxifen use 1
• Closed-angle glaucoma 1
• Uncontrolled hypertension (bupropion can elevate blood pressure and heart rate) 3, 2

Dose Adjustments for Special Populations

Hepatic Impairment:

• Moderate to severe impairment: Maximum 150 mg daily (one tablet total per day) 3, 2

Renal Impairment:

• Moderate to severe impairment (GFR <90 mL/min): Reduce total daily dose by 50% 3, 2

Common and Serious Side Effects

Common Side Effects (generally acceptable risk compared to continued smoking):

• Insomnia (24% vs 15% placebo)—administer second dose before 3 PM to minimize 1, 3, 4
• Dry mouth (13% vs 5% placebo) 1, 4
• Headache 1, 6
• Nausea 1, 6

Serious but Rare Side Effects:

• Seizures: Risk approximately 1 in 1,000 (0.1%) at 300 mg/day 1, 2, 7, 6
• Anaphylactic/hypersensitivity reactions: Risk approximately 1 in 1,000 to 1 in 10,000 2, 7
• Neuropsychiatric events: Recent high-quality evidence from the EAGLES trial (n=8,144) showed no significant increase in neuropsychiatric adverse events with bupropion compared to nicotine patch or placebo, even in patients with psychiatric disorders 1

Critical Monitoring Parameters

• Blood pressure and heart rate (bupropion can cause elevations) 3, 2
• Neuropsychiatric symptoms: Monitor for hostility, agitation, depressed mood, and suicidal ideation, especially in patients under 24 years 1, 2
• Discontinue immediately if signs of hostility, depression, or suicidal behavior emerge, weighing these risks against the substantial benefits of smoking cessation 1

Combination Therapy

Bupropion plus nicotine replacement therapy (NRT) shows the highest abstinence rates:

• 12-month abstinence: 35.5% with bupropion + NRT versus 30.3% with bupropion alone, though this difference was not statistically significant 1, 3
• Start NRT on the actual quit date (not when starting bupropion) 3
• Combination therapy side effects are similar to bupropion alone 1

Comparative Effectiveness with Alternative Therapies

Varenicline:

• Varenicline is superior to bupropion (28% vs 19% quit rates at 12 months) 2
• However, bupropion remains appropriate first-line therapy, particularly for patients with contraindications to varenicline or those preferring non-nicotine pharmacotherapy 1, 2

Nicotine Replacement Therapy:

• Bupropion and NRT have equivalent efficacy (relative risk 0.99) 2
• Bupropion offers the advantage of being oral and non-nicotine based 6

Nortriptyline:

• Similar efficacy to bupropion but considered second-line due to side effect profile 2

Behavioral Support Integration

Critical caveat: Published efficacy data for bupropion comes from trials that included behavioral support. 2, 7

Combine bupropion with structured behavioral counseling for optimal outcomes:

• Comprehensive programs with individualized counseling plus pharmacotherapy increase 6-month cessation rates from 6.8% to 21.3% compared to verbal advice alone 2
• Provide a definite quit date, weekly follow-up sessions for at least 4 weeks, and tailored self-help materials 2

Cost-Effectiveness

The estimated cost per life-year saved from bupropion treatment is approximately £1,000 or $1,500, making it a highly cost-effective intervention 7

Clinical Pearls and Common Pitfalls

• Do not start bupropion on the quit date—the 1-2 week lead time is essential for therapeutic drug levels 3
• Do not exceed 300 mg/day for smoking cessation to maintain the 0.1% seizure risk 1, 2
• Screen meticulously for seizure risk factors—any condition that lowers seizure threshold warrants extreme caution or avoidance 1, 2
• Bupropion efficacy is independent of depression history, but patients with depression may gain dual benefit 1, 2
• Re-treatment is effective in smokers who relapse after a previous course 5