What pharmacologic options are available for smoking cessation in an adult smoker who cannot or does not want to use varenicline?

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Pharmacologic Options for Smoking Cessation Beyond Varenicline

For adult smokers who cannot or will not use varenicline, nicotine replacement therapy (NRT) and bupropion SR are highly effective first-line alternatives, with combination NRT (patch plus a rapid-delivery form) offering the strongest efficacy among non-varenicline options. 1

First-Line Pharmacotherapy Options

Nicotine Replacement Therapy (NRT)

NRT increases smoking cessation rates by 60% compared to placebo (RR 1.60,95% CI 1.53-1.68), with all formulations demonstrating substantial benefit. 1

Individual NRT formulations ranked by efficacy:

  • Nicotine nasal spray: RR 2.02 (95% CI 1.49-2.73) 1
  • Oral tablets/lozenges: RR 1.95 (95% CI 1.61-2.36) 1
  • Nicotine inhaler: RR 1.90 (95% CI 1.36-2.67) 1
  • Transdermal patch: RR 1.64 (95% CI 1.52-1.78) 1
  • Nicotine gum: RR 1.49 (95% CI 1.40-1.60) 1

Combination NRT (patch + rapid-delivery form) is more effective than single-agent NRT (RR 1.34,95% CI 1.18-1.51), providing moderately improved cessation rates. 1

For highly nicotine-dependent smokers, 4 mg nicotine gum demonstrates significant benefit over 2 mg gum, though evidence for higher-dose patches is weaker. 1

Bupropion SR (Sustained-Release)

Bupropion SR increases smoking cessation rates at 6 months or longer compared to placebo (19.7% vs. 11.5%; RR 1.62,95% CI 1.49-1.76). 1

Bupropion SR combined with NRT provides additional benefit over bupropion SR alone (RR 1.24,95% CI 1.06-1.45), though it is not more effective than NRT alone. 1

Direct comparisons show no significant difference in abstinence rates between NRT and bupropion SR monotherapy. 1

Recommended Treatment Algorithm

Step 1: Select Initial Pharmacotherapy

For patients seeking maximum efficacy without varenicline:

  • First choice: Combination NRT (nicotine patch + gum, lozenge, nasal spray, or inhaler) 1
  • Alternative: Single-agent NRT (choose based on patient preference and tolerability) 1
  • Alternative: Bupropion SR (particularly if patient has comorbid depression or prefers oral medication) 1

Step 2: Integrate Mandatory Behavioral Support

All pharmacotherapy must be combined with behavioral counseling—medication alone is insufficient. 1

Minimum counseling requirements:

  • At least 4 sessions during the treatment period 1
  • Session duration: 10-30+ minutes, with longer sessions linked to higher success rates 1
  • First session: Within 2-3 weeks of starting medication 1

The 5 A's framework (Ask, Advise, Assess, Assist, Arrange) should guide counseling, with clear, personalized quit recommendations. 1

Step 3: Dosing and Duration

NRT dosing considerations:

  • Highly dependent smokers (≥20 cigarettes/day): Use 4 mg nicotine gum or higher-dose formulations 1
  • Combination NRT: Always pair patch (long-acting) with a rapid-delivery form (gum, lozenge, spray, or inhaler) 1
  • Duration: Standard treatment is 12 weeks, though NRT effectiveness is largely independent of therapy duration 1

Bupropion SR dosing:

  • Standard course is 12 weeks 1
  • Can be combined with NRT for enhanced efficacy 1

Step 4: Follow-Up Schedule

Arrange follow-up visits:

  • First visit: 2-3 weeks after starting pharmacotherapy to assess smoking status and medication tolerability 1
  • Subsequent visits: At 12 weeks and every 12 weeks if therapy is extended 1
  • At each visit: Assess risk of relapse and reinforce behavioral support 1

Step 5: Management of Treatment Failure

If patient fails to quit or relapses:

  • Continue or resume initial pharmacotherapy before switching 1
  • Consider switching to combination NRT if not already prescribed 1
  • Progressively intensify behavioral therapy with referral to specialty care as indicated 1
  • Address contributing factors: Frequent cravings, elevated anxiety/stress, living with smokers, substance use, inadequate behavioral support 1

Safety and Tolerability

NRT adverse effects are small and product-specific:

  • Patches: Skin irritation 2
  • Gum/tablets: Mouth irritation 2
  • No evidence that NRT increases risk of cardiovascular events, including heart attacks 2

Bupropion SR adverse effects are small overall, with insomnia being more common than with NRT (21.5% vs. 12.6% with placebo). 1

Behavioral interventions have small to no harms in nonpregnant adults. 1

Special Populations

Pregnant Women

Behavioral interventions are the only recommended approach for pregnant women, as they substantially improve smoking abstinence, increase infant birthweight, and reduce preterm birth risk. 1

Evidence on NRT, bupropion SR, and varenicline in pregnancy is inadequate, and the balance of benefits and harms cannot be determined. 1

Second-Line Options

Nortriptyline (tricyclic antidepressant) and clonidine (antihypertensive) are second-line agents reserved for patients who have failed or cannot tolerate first-line therapies, due to less favorable adverse effect profiles. 3

Common Pitfalls to Avoid

Do not prescribe pharmacotherapy without concurrent behavioral counseling—the combination is essential for optimal outcomes. 1

Do not underdose highly dependent smokers—use 4 mg nicotine gum or combination NRT rather than single low-dose formulations. 1

Do not abandon pharmacotherapy prematurely—continue or intensify treatment before switching to alternative agents. 1

Do not overlook the substantial benefit of combination NRT (patch + rapid-delivery form), which outperforms single-agent NRT. 1

References

1
Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

2
Research

Nicotine replacement therapy for smoking cessation.

The Cochrane database of systematic reviews, 2012

3
Research

Update on pharmacologic options for smoking cessation treatment.

The American journal of medicine, 2008

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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